Downregulation of the deubiquitinating enzyme USP10 correlates with neuronal apoptosis in HTLV-1-associated myelopathy

Shiho Arishima; Masahiko Takahashi; Mika Dozono; Takashi Yoshida; Satoshi Nozuma; Hiroshi Takashima; Masahiro Fujii; Ryuji Kubota

doi:10.1038/s41598-026-37271-x

. 2026 Jan 23;16:6062. doi: 10.1038/s41598-026-37271-x

Downregulation of the deubiquitinating enzyme USP10 correlates with neuronal apoptosis in HTLV-1-associated myelopathy

Shiho Arishima ¹, Masahiko Takahashi ², Mika Dozono ³, Takashi Yoshida ³, Satoshi Nozuma ³, Hiroshi Takashima ³, Masahiro Fujii ^2,^✉, Ryuji Kubota ^1,^✉

PMCID: PMC12901015 PMID: 41577957

Abstract

Human T-cell leukemia virus type 1–associated myelopathy (HAM) is a chronic neuroinflammatory disease characterized by spinal cord neuronal loss. The mechanisms underlying this degeneration remain unclear. We investigated the role of ubiquitin-specific peptidase 10 (USP10), a regulator of oxidative stress and apoptosis, in HAM pathogenesis. Spinal cord tissues from eight HAM patients and two healthy controls (HCs) were analyzed by immunohistochemistry. We assessed USP10 expression, neuronal density (NeuN), apoptotic markers (TUNEL, active caspase-3), and p62, a stress-responsive regulator of autophagy and apoptosis. USP10 expression was markedly reduced in HAM neurons compared to HCs. This downregulation was associated with increased neuronal apoptosis and decreased NeuN-positive cell density, particularly among large neurons, and some surviving neurons showed diminished NeuN immunoreactivity. Reduced p62 expression was also observed in cases with low USP10 and high apoptotic activity. Notably, one HAM patient with preserved USP10 and p62 expression exhibited minimal neuronal loss and mild neurological symptoms. Although exploratory, this study supports an association between downregulation of USP10 and reduced p62 levels, and neuronal apoptosis and loss in HAM, and highlights USP10 as a potential regulator of neuronal survival, and a promising diagnostic or prognostic marker and a future therapeutic pathway in virus-induced neuroinflammation.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-37271-x.

Keywords: HTLV-1, HTLV-1-associated myelopathy, Spinal cord, Neuron, USP10, Apoptosis

Subject terms: Cell biology, Neurology, Neuroscience

Introduction

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus belonging to the Deltaretrovirus genus of the Retroviridae family. It is globally distributed and is estimated to infect 10–20 million individuals worldwide¹. HTLV-1 infection can lead to adult T-cell leukemia (ATL), a hematological malignancy, and HTLV-1-associated myelopathy (HAM), a progressive and debilitating neuroinflammatory disorder^2–4. HAM is characterized by chronic inflammation of the central nervous system (CNS) and manifests clinically as spastic paraparesis, bladder dysfunction, and sensory disturbances, primarily affecting the lower extremities⁵. The disease typically follows a slowly progressive course.

Pathological features observed in the spinal cords of patients with HAM include perivascular lymphocytic infiltration, demyelination, and neuronal loss⁶. These infiltrating cells are composed predominantly of HTLV-1-infected lymphocytes and HTLV-1-specific cytotoxic T lymphocytes (CTLs), suggesting an ongoing immune response directed against infected cells within the CNS⁷. Importantly, although HTLV-1-infected lymphocytes are present in the spinal cord, direct HTLV-1 infection of neurons has not been demonstrated in patients with HAM^7–9. It is therefore widely believed that neuronal damage results primarily from immune-mediated mechanisms. CTLs targeting HTLV-1-infected cells release proinflammatory cytokines and neurotoxic mediators which, although directed at infected lymphocytes, can also damage surrounding neural cells, leading to demyelination and neuronal loss^10,11. This persistent inflammatory environment is thought to play a central role in the progressive neurological deterioration observed in HAM. Despite extensive research, the precise mechanisms underlying neuronal loss in HAM remain incompletely understood, and no effective curative therapies have been established.

Ubiquitin-specific peptidase 10 (USP10) is a deubiquitinating enzyme that removes ubiquitin chains from ubiquitin-conjugated protein substrates and plays a critical role in various cellular processes, including protein homeostasis, apoptosis, and autophagy^12–14. USP10 is ubiquitously expressed in multiple cell types, including neurons. It has been implicated in the pathogenesis of several neurodegenerative and neuroinflammatory disorders, such as Parkinson’s disease and ischemic stroke, which are accompanied by prominent neuroinflammation. Parkinson’s disease is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra, resulting in motor dysfunction and cognitive decline. In vitro studies have shown that USP10 depletion enhances apoptosis in cultured dopaminergic neurons following dopamine exposure¹⁵. Furthermore, USP10 knockout in mice exacerbates neuroinflammation and neuronal apoptosis in models of cerebral ischemia–reperfusion injury¹⁶. These findings underscore the neuroprotective function of USP10 in preventing neuronal loss and suppressing inflammation in the CNS. However, the role of USP10 in virus-associated neuroinflammatory diseases such as HAM has not been elucidated.

We hypothesized that USP10 may be involved in the neuronal loss observed in the spinal cords of patients with HAM and that its downregulation may contribute to disease-associated neurological dysfunction. To address this, we performed immunohistochemical analyses of spinal cord tissue from HAM patients and HCs, focusing on USP10 expression, neuronal density, neuronal apoptosis, and p62 expression. Our observations indicate that USP10 immunoreactivity is frequently reduced in HAM spinal cords and that this reduction is associated with increased neuronal apoptosis and decreased NeuN-positive neuron counts. Although causality cannot be established from this autopsy series, the data support the relevance of USP10-related pathways as potential contributors to neuronal loss in HTLV-1-induced neuroinflammation.

Results

USP10 expression in the spinal cords of HAM patients

USP10 expression in the spinal cords of HAM patients and HCs was evaluated by immunohistochemistry. Representative staining patterns are shown in Fig. 1a–c. Neurons were identified morphologically by their large, pyramidal or oval-shaped cell bodies, lightly stained nuclei, and Nissl substance in the cytoplasm. In HCs, USP10 was ubiquitously expressed across spinal cord cells, with strong staining observed in neurons (Fig. 1a). In most HAM patients, USP10 expression in spinal cord neurons was reduced but still clearly detectable, while one patient (#9535) showed minimal expression (Fig. 1b–c). The intensity of USP10 staining in neurons was graded on a three-point scale: 2 (strong), 1 (moderate), and 0 (weak), as summarized in Table 1. Patient #9535 was graded as 0, patient #8838 exhibited strong USP10 staining (grade 2) comparable to that in HCs (grade 2), and the remaining six patients with HAM showed reduced USP10 expression (grade 1). On average, USP10 staining grades were lower in HAM patients than in HCs. However, given the small number of controls, these differences are described descriptively rather than subjected to formal statistical testing (Fig. 1d).

Fig. 1 — USP10 expression in the spinal cords of HAM patients. In most HAM patients, USP10 expression in spinal cord neurons was reduced but still clearly detectable, while one patient (#9535) showed minimal expression. USP10 immunoreactivity was graded on a three-point scale: 2 (strong), 1 (moderate), and 0 (weak). Representative images are shown for: (a) a healthy control (HC, sample #621, grade 2); (b) a HAM patient (sample #6115, grade 1); and (c) a HAM patient (sample #9535, grade 0). Neurons were identified by their morphology, including pyramidal or oval shape and granular cytoplasm (indicated by arrowhead). (d) Comparison of USP10 staining grades between HCs (N = 2) and HAM patients (N = 8), shown as mean ± SD. Comparison between the two groups was not performed due to the limited number of control samples.

Table 1.

Summary of tissue staining results.

Patient ID	Category	USP10 staining*	TUNEL+ count**	Cas-3+ frequency^†	NeuN+ count**	P62 staining*
621	HC	2	0	1	74	1
622	HC	2	0	1	65	1
8838	HAM	2	1	3	84	2
994	HAM	1	11	3	37	1-2
676	HAM	1	6	2	36	0-1
8644	HAM	1	6	3	34	1
6315	HAM	1	3	3	11	1
8624	HAM	1	13	3	2	0
6115	HAM	1	8	3	0	0-1
9535	HAM	0	3	1	10	0

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*USP10 and p62 expression levels were graded on a three-point scale: grade 2 (strong), grade 1 (moderate), and grade 0 (weak). **Counts of nuclear TUNEL-positive neurons and NeuN-positive neurons were obtained from consistent regions across all samples. ^†The frequency of active caspase-3-positive neurons was determined in anatomically matched regions.

Neuronal apoptosis in the spinal cords of HAM patients

To investigate neuronal apoptosis in HAM, we performed a TUNEL assay to detect DNA fragmentation, a hallmark of apoptosis (Fig. 2a–b). The number of nuclear TUNEL-positive cells was prominently increased in HAM patients, whereas no such cells were detected in HCs (Table 1). On average, the percentage of nuclear TUNEL-positive neurons among neurons with detectable nuclei was 74.7 ± 26.8% in HAM patients, compared to 0.0 ± 0.0% in HCs (Fig. 2c). Furthermore, the percentage was significantly higher in the moderate USP10 staining group (grade 1, N = 6) than in the strong staining group (grade 2, N = 3) (Fig. 2d; P = 0.024, Mann–Whitney U test), suggesting an inverse association between USP10 expression and apoptotic burden across the HAM and HC samples. These findings indicate that enhanced neuronal apoptosis, as demonstrated by TUNEL staining, was observed in HAM patients, but not in HCs (Fig. 2c). To confirm these observations, we next evaluated apoptotic activity using active caspase-3 as an early apoptosis marker. Representative images of active caspase-3–positive neurons are shown in Figs. 2e–h. In HCs, only a few neurons exhibited weak caspase-3 staining (Fig. 2e), whereas HAM patients showed variable frequencies of active caspase-3-positive neurons, ranging from low (Fig. 2f) to moderate (Fig. 2g) and high (Fig. 2h). Semi-quantitative grading results are summarized in Table 1. All HAM cases, except for #9535, demonstrated increased frequencies of active caspase-3–positive neurons. On average, active caspase-3–positive neurons were more frequent in HAM patients than in HCs (Fig. 2i), consistent with the TUNEL results. The frequency of caspase-3–positive neurons tended to be higher in samples with moderate USP10 expression (grade 1) than in those with strong USP10 expression (grade 2), as shown in Fig. 2j, again supporting an inverse relationship between USP10 levels and apoptotic activity, although these analyses are exploratory and limited by the sample size. Collectively, these two complementary approaches for detecting tissue apoptosis indicate that neuronal apoptosis is a prominent pathological feature of HAM and that reduced USP10 expression is associated with enhanced apoptotic activity.

Neuronal cell density in the spinal cords of HAM patients

Neuronal cell density was assessed by NeuN immunostaining. NeuN-positive neurons were counted in three randomly selected, non-overlapping fields at ×100 magnification within the anterior horn gray matter. Representative NeuN staining patterns are shown in Fig. 3a–c, and the quantitative data are summarized in Table 1. In an HC sample (#621), a high density of strongly NeuN-positive neurons was observed (Fig. 3a), with 74 neurons counted in three randomly selected areas (Table 1). In contrast, spinal cords from HAM patients exhibited a marked reduction in large neurons and a heterogeneous neuronal population with varying levels of NeuN immunoreactivity, ranging from grade 2 (strong) to grade 0 (weak) (Figs. 3b [grade 1] and 3c [grade 0]), resulting in an overall decrease in neuronal counts. NeuN-negative neurons were identified based on characteristic morphological features, such as pyramidal or oval-shaped cell bodies with granular cytoplasm and were predominantly small neurons. The number of large neurons was reduced in HAM patients, while the remaining neurons frequently exhibited diminished NeuN immunoreactivity. Therefore, only NeuN-positive neurons were quantified. Most HAM samples showed a reduction in NeuN-positive neurons, except for sample #8838, which exhibited a count of 84 neurons (Table 1). Across all samples, counts of NeuN-positive neurons were lower in HAM patients than in HCs (Fig. 3d) on average. Samples with strong USP10 expression (grade 2) had significantly higher counts of NeuN-positive neurons than those with moderate expression (grade 1) (P = 0.024, Fig. 3e), whereas statistical comparison with grade 0 was not performed because only one case (#9535) was in this category. Overall, NeuN-positive cell counts declined in proportion to the reduced USP10 expression in HAM patients (Fig. 3f). These results suggest that reduced USP10 expression is associated with lower neuronal density in HAM patients.

Fig. 3 — Neuronal cell density in the spinal cords of HAM patients. NeuN-positive neurons were quantified in consistent regions across samples. Representative images are shown for: (a) an HC (sample #621) with grade 2 (strong) USP10 staining, in which 74 NeuN-positive neurons were counted in three randomly selected areas at ×100 magnification within the anterior horn gray matter; (b) a HAM patient (#8644) with grade 1 (moderate) USP10 staining and 34 NeuN-positive neurons; and (c) a HAM patient (#9535) with grade 0 (weak) USP10 staining and 10 NeuN-positive neurons. NeuN-negative neurons were identified by their morphology, including pyramidal or oval shape and granular cytoplasm (indicated by arrowheads), and were frequently observed in HAM patients. (d) Comparison of NeuN-positive neuron counts between HCs (N = 2) and HAM patients (N = 8), presented as mean ± SD. (e) Comparison of NeuN-positive neuron counts across USP10 staining grades among all samples. The grade 0 group contains only one patient; therefore, comparisons were performed between the grade 1 and grade 2 groups using a two‑tailed Mann–Whitney U test, yielding an exact P value of 0.024. (f) Distribution of NeuN-positive neurons among HAM patients according to USP10 staining grade (grade 2: N = 1; grade 1: N = 6; grade 0: N = 1). Comparative analysis was not performed due to the small sample size.

p62 expression in the spinal cords of HAM patients

p62/sequestosome 1 (SQSTM1) is a multifunctional protein involved in autophagy and regulation of apoptosis¹⁷. p62 has been shown to inhibit apoptosis in cells treated with proteasome inhibitors in coordination with USP10¹⁸. Representative p62 staining patterns are shown in Figs. 4a–c. In HCs, moderate p62 staining was observed throughout the spinal cord (Table 1). Among HAM patients, one case (#8838) exhibited strong p62 staining (Fig. 4a), whereas other cases showed moderate to weak staining (Fig. 4b and c), with staining intensities summarized in Table 1. Although mean p62 staining grades did not differ markedly between HAM and HC groups (Fig. 4d), HAM samples with reduced USP10 expression tended to show lower p62 levels (Fig. 4e). Importantly, cases with low p62 expression (#676, #8624, #6115, and #9535) also exhibited reduced numbers of NeuN-positive neurons (Table 1), suggesting that reduced p62 may be associated with neuronal loss in HAM patients. These observations are consistent with the proposed cooperative role of USP10 and p62 in suppressing apoptosis and maintaining neuronal survival under chronic inflammatory stress.

Fig. 4 — A p62 expression in the spinal cords of HAM patients. The intensity of p62 staining was graded on a three-point scale: grade 2 (strong), grade 1 (moderate), and grade 0 (weak). Representative images are shown for: (a) a HAM patient (#8838, grade 2); (b) a HAM patient (#8644, grade 1); and (c) a HAM patient (#9535, grade 0). (d) Comparison of p62 staining grades between HCs (N = 2) and HAM patients (N = 8), shown as mean ± SD. (e) Relationship between USP10 and p62 staining grades across all samples (USP10 grade 2: N = 3; grade 1: N = 6; grade 0: N = 1).

Correlation analyses among USP10 expression, neuronal apoptosis, p62 expression, and neuronal cell density in HAM spinal cords

To integrate these observations, we summarized USP10 staining grade, TUNEL-positive neuron counts, p62 staining grade, and NeuN-positive neuron counts for each subject (Table 1). In seven of eight HAM patients (excluding #8838), USP10 expression and NeuN-positive neuron counts were reduced, while p62 expression was generally low or moderate. The most pronounced neuronal loss was observed in cases #8624 and #6115, both of which exhibited numerous TUNEL–positive neurons and low p62 expression. In contrast, patient #8838 showed preserved USP10 and p62 expression, minimal neuronal loss, and relatively mild clinical disability. To further explore the relationships among these factors, we performed Spearman’s rank correlation analyses in HAM patients (N = 8) and HCs (N = 2) (Fig. 5). A significant positive correlation was observed between USP10 staining grade and NeuN-positive neuron counts (R = 0.82, P = 0.020), as well as NeuN-positive neuron counts and p62 staining grade (R = 0.73, P = 0.020). Trends toward positive correlations were also noted between USP10 staining grade and p62 staining grade (R = 0.65, P = 0.065), and between TUNEL-positive neuron counts and the frequency of caspase-3-neurons (R = 0.61, P = 0.053). Conversely, trends toward negative correlations were observed between USP10 staining grade and TUNEL-positive neuron counts (R = -0.47, P = 0.067), and between TUNEL-positive neuron counts and NeuN-positive neuron counts (R = -0.64, P = 0.052). Taken together, these findings support a model in which downregulation of USP10 and p62 is associated with increased neuronal apoptosis and loss of neurons in HAM patients.

Fig. 5 — Correlation analyses among USP10 expression, neuronal apoptosis, p62 expression, and neuronal cell density in HAM spinal cords. Scatter plots illustrate pairwise relationships among USP10 staining grade, NeuN-positive neuron counts, TUNEL-positive neuron counts, the frequency of active caspase-3–positive neurons, and p62 staining grade in patients with HAM (N = 8) and healthy controls (HC; N = 2). Each dot represents one case. Spearman’s rank correlation coefficients (R) and the corresponding two-tailed P values were calculated across all cases and are shown in each panel.

Discussion

In this autopsy-based study, we investigated the potential involvement of USP10 in neuronal loss in HAM by analyzing USP10 expression, neuronal apoptosis, and neuronal density in spinal cord tissues from HAM patients and HCs. Our findings revealed a marked reduction in USP10 expression in spinal cord neurons of HAM patients compared to HCs (Fig. 1). Consistently, TUNEL-positive and active caspase-3–positive neurons were more frequently detected in HAM patients than in HCs (Fig. 2c and i), indicating that neuronal apoptosis is a key pathological feature of HAM. Moreover, the significant increase in TUNEL-positive cells in HAM samples with reduced USP10 expression suggests a potential inverse relationship between USP10 expression and neuronal apoptosis in HAM patients (Fig. 2d). NeuN-positive neuronal counts were also significantly lower in HAM patients than in HCs (Fig. 3). Seven of eight HAM patients, with the exception of　patient #8838, exhibited both decreased USP10 expression and reduced numbers of NeuN-positive neurons (Table 1), further supporting the association between USP10 downregulation and neuronal loss. The most pronounced neuronal loss was observed in cases #8624 and #6115, both of which exhibited abundant TUNEL–positive neurons (Figs. 2b). In contrast, patient #8838, who maintained strong USP10 expression, exhibited minimal neuronal loss, further supporting the notion of a neuroprotective role of USP10 (Table 1). Interestingly, despite a disease duration of 22 years, this patient presented with relatively mild neurological symptoms associated with HAM, requiring only a cane for ambulation (Table 2). These mild impairments correlated with neuronal preservation, sustained USP10 expression, and limited neuronal apoptosis in the spinal cord.

Table 2.

Clinical characteristics of study subjects.

Patient ID	Category*	Age/Sex	Duration of disease (years)	Cause of death	Cellular infiltration**
621	HC	70/F	NA^†	Hepatoma	–
622	HC	70/M	NA	Hepatoma	–
8838	HAM	75/F	22	Pancreas carcinoma	+
994	HAM	84/F	18	Interstitial pneumonia	+–
676	HAM	72/F	20	Bacterial pneumonia	++
8644	HAM	74/F	14	Interstitial pneumonia	+–
6315	HAM	71/F	4.5	Bacterial pneumonia	++
8624	HAM	59/M	7	Pulmonary tuberculosis	++
6115	HAM	68/F	9	Cholecystitis	+–
9535	HAM	47/M	17	Virus-associated hemophagocytic syndrome	+–

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*HC, neurologically healthy control; HAM, HTLV-1-associated myelopathy. **Assessment of cellular infiltration: ‘–’ indicates no infiltration; ‘+–’, mild; ‘+’, moderate infiltration; and ‘++’, severe infiltration. ^†NA, not applicable.

USP10 is a ubiquitin-specific protease that regulates protein homeostasis and promotes cell survival across various tissues¹². In the nervous system, USP10 has been implicated in neurodegenerative and neuroinflammatory conditions. For instance, USP10 promotes cytoprotective aggresome formation in cultured cells and inhibits apoptosis¹⁸, and mediates neuroprotection in ischemic stroke by suppressing NF-κB signaling¹⁹. Moreover, USP10 reduces the level of reactive oxygen species (ROS) in neuronal cells treated with dopamine and inhibits ROS-dependent apoptosis¹⁵. These observations suggest that USP10 may contribute to neuronal survival in various neurodegenerative and inflammatory diseases through distinct, disease-specific mechanisms. Consistent with these findings, our data demonstrate that USP10 downregulation in the spinal cords of HAM patients is associated with enhanced neuronal apoptosis, implying a neuroprotective role of USP10 in virus-induced neuroinflammation.

Neuropathologically, HAM is characterized by perivascular lymphocytic infiltration, demyelination, and neuronal loss. The infiltrating immune cells largely consist of HTLV-1–infected lymphocytes and virus-specific CTLs, which are thought to mediate bystander neuronal damage via proinflammatory mediators^7,10. Although direct infection of neurons by HTLV-1 has not been demonstrated^7–9, virus–specific CTLs and infected lymphocytes secrete inflammatory cytokines such as TNF-α and IL-1β ²⁰, which can induce neurotoxicity through oxidative stress and apoptotic signaling^21,22. These cytokines are consistently detected in the spinal cords of HAM patients^7,23, and are known to be produced by HTLV-1–specific CTLs²⁴. TNF-α, for instance, activates cyclin-dependent kinase 5, thereby enhancing ROS production and contributing to neuronal dysfunction²⁵. USP10 has been shown to interact with HTLV-1 oncoprotein Tax in HTLV-1-infected T cells and to suppress apoptosis in infected cells²⁶. However, since HTLV-1 infection of neurons has not been demonstrated, it is unlikely that the reduction of USP10 expression observed in the neurons of HAM patients is due to a Tax-dependent mechanism. Instead, it is more plausible that USP10 downregulation in neurons of HAM patients results from inflammation-associated oxidative stress. ROS have been shown to inhibit the transcription of several deubiquitinating enzymes²⁷, supporting the plausibility of this mechanism in the reduced expression of USP10 in HAM.

USP10 has been reported to interact with p62/SQSTM1, a multifunctional adaptor protein involved in apoptosis, autophagy, redox regulation, and NF-κB signaling, and these two proteins function cooperatively^18,28. The interaction between USP10 and p62 is known to suppress apoptosis under stress conditions, including proteasome inhibition¹⁸. In our study, diminished USP10 expression in HAM patients was accompanied by lower p62 levels and a decrease in NeuN-positive neuron counts, whereas patient #8838, with preserved USP10 and relatively high p62 levels, exhibited maintained neuronal integrity. These observations support the hypothesis that USP10 and p62 act synergistically to counteract oxidative stress and protect neurons from apoptosis in the inflamed spinal cords in HAM patients.

In the spinal cords of HAM patients, we observed an increased number of NeuN-negative neurons, accompanied by a marked reduction in large NeuN-positive motor neurons. NeuN is typically expressed in the majority of mature neurons²⁹. Previous studies have reported the appearance of NeuN-negative neurons in ischemic brain tissue³⁰. Therefore, the widespread increase in NeuN-negative neurons in HAM implies that these neurons in HAM are experiencing stress or damage while maintaining their morphological integrity. Notably, this phenomenon was associated with reduced expression of USP10, a critical regulator of oxidative stress responses and apoptosis¹². Given this concomitant downregulation of NeuN and USP10, we propose that chronic inflammation in the spinal cord, triggered by HTLV-1 infection, leads to the suppression of USP10 expression. This suppression may contribute to widespread neuronal dysfunction and apoptosis, ultimately resulting in the loss of NeuN expression in a subset of neurons. These findings highlight the multifactorial mechanisms underlying neuronal damage in HAM, characterized by both selective neuronal loss and functional impairment of surviving neurons. Furthermore, our observations extend previous reports, which have predominantly emphasized apoptosis of infiltrating T cells and oligodendrocytes within HAM spinal lesions^7,31, by highlighting neuronal apoptosis and dysfunction as potentially more prominent pathological features than previously recognized.

Two prior studies have demonstrated downregulation of USP10 in neurodegenerative diseases. We recently reported that USP10 protein levels are decreased in the late stage of Alzheimer’s disease (AD) (Braak stage VI), and that this reduction correlates with increased apoptosis, as evidenced by elevated active caspase-3 expression in affected brain regions³². In addition, Guise et al. showed that USP10 protein levels are reduced in patients with amyotrophic lateral sclerosis (ALS)³³. Both AD and ALS are chronic neurodegenerative disorders characterized by substantial neuronal apoptosis in the regions most affected. Taken together, these observations suggest that USP10 downregulation may represent a shared molecular mechanism contributing to neuronal apoptosis across multiple chronic neurodegenerative diseases.

Although both the TUNEL assay and active caspase-3 staining indicated enhanced apoptosis in HAM patients compared to HCs, the results showed slight discrepancies, as illustrated in Fig. 2. The TUNEL assay revealed no evidence of apoptotic neurons in HCs (Fig. 2c), whereas active caspase-3 staining detected a small number of positive cells (Fig. 2i). Although active caspase-3 is a key marker of apoptosis, its expression has been reported under non-lethal or physiological stress conditions^34,35. Therefore, active caspase-3 staining may reflect non-apoptotic or reversible processes. Furthermore, both TUNEL-positive and active caspase-3–positive neurons were less frequent in the sample with weak USP10 expression (grade 0) than in those with moderate expression (grade 1), as shown in Fig. 2d and j respectively. This finding was unexpected, as we had hypothesized that lower USP10 expression would be associated with greater levels of apoptosis, given the proposed neuroprotective role of USP10. However, as the grade 0 sample corresponded to a single case (#9535 in Table 1), in which the number of NeuN-positive neurons was markedly reduced. It is therefore possible that apoptosis had progressed to a later stage in this patient, suggesting that many apoptotic neurons may have already undergone late-stage degeneration and disintegration, rendering them undetectable by histological analysis.

Several limitations of our study must be emphasized. First, the sample size is small, particularly for controls, reflecting the limited availability of autopsy spinal cord tissue with detailed clinical information. As a result, our statistical power is limited, and our analyses are exploratory. We report exact P values where tests were performed but interpret them cautiously. Second, our data are based entirely on immunohistochemistry and semi-quantitative grading. We did not perform independent quantitative validation of USP10 expression in CSF, or tissue lysates (e.g. by ELISA, Western blot, or qPCR), and we did not perform Western blot confirmation of antibody specificity in this cohort. Third, tissues were fixed in 4% paraformaldehyde according to routine autopsy protocols, and detailed fixation times and post-mortem intervals were not uniformly available. These factors can influence antigen preservation and staining intensity and are likely to contribute additional variability. Fourth, our control subjects died of hepatocellular carcinoma. Although they had no clinical or pathological evidence of CNS disease, systemic malignancy and prior treatments could theoretically influence systemic inflammatory or apoptotic pathways; subtle effects on spinal cord markers cannot be excluded. Finally, our autopsy-based design provides only a single time point per patient and does not allow assessment of temporal changes in USP10, p62, or neuronal apoptosis over the clinical course of HAM.

In summary, our findings demonstrate that USP10 immunoreactivity is frequently reduced in the spinal cords of patients with HAM and that this reduction is associated with increased neuronal apoptosis, reduced NeuN-positive neuron counts, and altered p62 expression. These observations support the hypothesis that an USP10–p62 axis contributes to neuronal degeneration in HAM. Because of the limitations described above, our data should be interpreted as evidence of correlation rather than a direct causal effect. Nevertheless, they identify USP10-related pathways as a plausible mechanistic link between chronic neuroinflammation and neuronal loss, and support further investigation of USP10 as a potential diagnostic or prognostic marker and a future therapeutic pathway in virus-induced neuroinflammatory diseases.

Materials and methods

Subjects

Autopsy spinal cord samples were obtained from eight patients with HAM and two neurologically healthy controls (HCs), with informed consent from their families. The diagnosis of HAM in patients was confirmed according to established clinical and laboratory criteria. Control subjects had no history of neurological disease and showed no pathological abnormalities in the spinal cord at autopsy, although both died of hepatocellular carcinoma. All available thoracic spinal cord blocks from such controls with sufficient tissue quality were included. The clinical characteristics of the subjects are summarized in Table 2. Spinal cord tissues were fixed in 4% paraformaldehyde, which was consistently applied across both HAM and control groups. Post-mortem intervals before autopsy were within 10 h, and tissues were fixed in 4% paraformaldehyde for 48 h at 4 °C, after which thoracic spinal cord blocks were paraffin-embedded. This study was approved by the Ethics Committee of Kagoshima University (approval number: G491).

Immunohistochemical analysis

Paraffin-embedded sections were cut to a thickness of 6 μm, deparaffinized, and treated to block endogenous peroxidase activity. The relatively thick section size (6 μm) was chosen to ensure adequate representation of large anterior horn neurons and to maximize axonal tracing. Optimal antigen retrieval conditions were determined for each antibody in preliminary experiments. After antigen retrieval, sections were blocked with 5% normal goat serum and incubated with primary antibodies overnight at 4 °C. After washing, sections were incubated with a polymer-conjugated secondary antibody (Nichirei, Tokyo, Japan) at room temperature for 30 min. For chromogenic detection, 3,3’-diaminobenzidine (DAB; Agilent, Santa Clara, USA) was used for USP10 and active caspase-3 staining, while aminoethyl carbazole (AEC; Vector Laboratories, California, USA) was used for NeuN and p62 staining. Nuclear counterstaining was performed with hematoxylin. Neurons were identified based on morphological criteria, including a large cell body with pyramidal or oval shape, a lightly stained, prominent nucleus, and Nissl substance in the cytoplasm³⁶. NeuN immunostaining was used as an alternative marker for neuronal identification²⁹. Negative control sections processed with isotype control antibodies were included in each staining run to monitor non-specific background (Supplementary File 1). Details of the primary antibodies, including suppliers, catalog numbers, and lot numbers where available, are provided in a Supplementary File 2.

Evaluation of staining results

We perform semi‑quantitative grading (USP10, p62, caspase‑3) and quantitative counts (NeuN‑positive and TUNEL‑positive neurons). USP10 and p62 expressions in anterior horn neurons were graded by staining intensity: ‘2’ for strong, ‘1’ for moderate, and ‘0’ for weak staining. The frequency of active caspase-3-positive neurons was assessed within the anterior horn gray matter of spinal cord sections and graded as: ‘3’ for high, ‘2’ for moderate, and ‘1’ for low frequency. NeuN-positive neurons were manually counted under a light microscope at ×100 magnification. Counts were obtained from three randomly selected fields within neuron-dense regions of the anterior horn gray matter. Evaluations were performed in a blinded manner by two independent researchers. An OLYMPUS BX43 microscope was used, and digital images were acquired with cellSens Standard software (OLYMPUS, Tokyo, Japan).

TUNEL assay

To detect apoptosis at the molecular level, we performed a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. The procedure was conducted according to the manufacturer’s instructions (ApopTag, Merck Millipore, Burlington, USA). DNA fragmentation, a hallmark of apoptosis, was visualized using DAB as the chromogenic substrate. Nuclear TUNEL-positive neurons were manually counted under a light microscope at ×100 magnification in three randomly selected fields within regions of high neuronal density in the anterior horn gray matter.

Statistics

Because of the small sample size, particularly in the healthy control (HC) group, statistical analyses were exploratory. Robust hypothesis testing was not feasible given the limited number of controls (N = 2); therefore, comparisons between HAM and HC groups are presented primarily as descriptive statistics. For analyses stratified by USP10 staining grade, the grade 0 group contained only one sample, so the remaining two groups (grades 1 and 2) were compared using the two-tailed Mann–Whitney U test. Exact P values were reported for all analyses to account for the small sample size. Correlation analyses were performed using Spearman’s rank correlation. Statistical significance was defined as P < 0.05.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1^{(85.9KB, pdf)}

Supplementary Material 2^{(252.7KB, pdf)}

Author contributions

S.A. performed the experiments, analyzed the data, prepared the figures, and drafted the manuscript. M.T. contributed to study design and manuscript preparation. M.F. and R.K. designed and supervised the study and contributed to manuscript preparation. M.D., T.Y., S.N., and H.T. collected clinical samples and associated clinical data. All authors reviewed and approved the final version of the manuscript.

Funding

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 23K24380).

Data availability

The dataset supporting the conclusions of this article is included within the article and its additional file.

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Kagoshima University (approval date: 24 June 2021; approval number: G491). Written informed consent was obtained from the patients’ family members.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Masahiro Fujii, Email: fujiimas@med.niigata-u.ac.jp.

Ryuji Kubota, Email: kubotar@m2.kufm.kagoshima-u.ac.jp.

References

1.Gessain, A. & Cassar, O. Epidemiological aspects and world distribution of HTLV-1 infection. Front. Microbiol.3, 388 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Uchiyama, T., Yodoi, J., Sagawa, K., Takatsuki, K. & Uchino, H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood50, 481–492 (1977). [PubMed] [Google Scholar]
3.Gessain, A. et al. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet2, 407–410 (1985). [DOI] [PubMed] [Google Scholar]
4.Osame, M. et al. HTLV-I associated myelopathy, a new clinical entity. Lancet1, 1031–1032 (1986). [DOI] [PubMed] [Google Scholar]
5.Osame, M. et al. Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemialike cells. Ann. Neurol.21, 117–122 (1987). [DOI] [PubMed] [Google Scholar]
6.Umehara, F. et al. Immunocytochemical analysis of the cellular infiltrate in the spinal cord lesions in HTLV-I-associated myelopathy. J. Neuropathol. Exp. Neurol.52, 424–430 (1993). [DOI] [PubMed] [Google Scholar]
7.Matsuura, E., Kubota, R., Tanaka, Y., Takashima, H. & Izumo, S. Visualization of HTLV-1-specific cytotoxic T lymphocytes in the spinal cords of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. J. Neuropathol. Exp. Neurol.74, 2–14 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Moritoyo, T. et al. Human T-lymphotropic virus type I-associated myelopathy and tax gene expression in CD4 + T lymphocytes. Ann. Neurol.40, 84–90 (1996). [DOI] [PubMed] [Google Scholar]
9.Matsuoka, E. et al. Perivascular T cells are infected with HTLV-I in the spinal cord lesions with HTLV-I-associated myelopathy/tropical spastic paraparesis: double staining of immunohistochemistry and polymerase chain reaction in situ hybridization. Acta Neuropathol.96, 340–346 (1998). [DOI] [PubMed] [Google Scholar]
10.Ijichi, S. et al. An autoaggressive process against bystander tissues in HTLV-I-infected individuals: a possible pathomechanism of HAM/TSP. Med. Hypotheses. 41, 542–547 (1993). [DOI] [PubMed] [Google Scholar]
11.Nozuma, S., Kubota, R. & Jacobson, S. Human T-lymphotropic virus type 1 (HTLV-1) and cellular immune response in HTLV-1-associated myelopathy/tropical spastic paraparesis. J. Neurovirol.26, 652–663 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Bhattacharya, U., Neizer-Ashun, F., Mukherjee, P. & Bhattacharya, R. When the chains do not break: the role of USP10 in physiology and pathology. Cell. Death Dis.11, 1033 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Jia, R. & Bonifacino, J. S. The ubiquitin isopeptidase USP10 deubiquitinates LC3B to increase LC3B levels and autophagic activity. J. Biol. Chem.296, 100405 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Ye, Z., Chen, J., Huang, P., Xuan, Z. & Zheng, S. Ubiquitin-specific peptidase 10, a deubiquitinating enzyme: assessing its role in tumor prognosis and immune response. Front. Oncol.12, 990195 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Sango, J. et al. USP10 inhibits the dopamine-induced reactive oxygen species-dependent apoptosis of neuronal cells by stimulating the antioxidant Nrf2 activity. J. Biol. Chem.298, 101448 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Wang, L., Wu, D. & Xu, Z. USP10 protects against cerebral ischemia injury by suppressing inflammation and apoptosis through the Inhibition of TAK1 signaling. Biochem. Biophys. Res. Commun.516, 1272–1278 (2019). [DOI] [PubMed] [Google Scholar]
17.Alegre, F. et al. Role of p62/SQSTM1 beyond autophagy: a lesson learned from drug-induced toxicity in vitro. Br. J. Pharmacol.175, 440–455 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Takahashi, M. et al. USP10 is a driver of ubiquitinated protein aggregation and aggresome formation to inhibit apoptosis. iScience9, 433–450 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Xie, C., Gao, X., Liu, G., Tang, H. & Li, C. USP10 is a potential mediator for vagus nerve stimulation to alleviate neuroinflammation in ischaemic stroke by inhibiting NF-kappaB signalling pathway. Front. Immunol.14, 1130697 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Tendler, C. L. et al. Cytokine induction in HTLV-I associated myelopathy and adult T-cell leukemia: alternate molecular mechanisms underlying retroviral pathogenesis. J. Cell. Biochem.46, 302–311 (1991). [DOI] [PubMed] [Google Scholar]
21.Gong, Y. et al. Inhibition of the NKCC1/NF-kappaB signaling pathway decreases inflammation and improves brain edema and nerve cell apoptosis in an SBI rat model. Front. Mol. Neurosci.14, 641993 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Ye, L. et al. IL-1beta and TNF-alpha induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J. Neurochem.125, 897–908 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Umehara, F. et al. Cytokine expression in the spinal cord lesions in HTLV-I-associated myelopathy. J. Neuropathol. Exp. Neurol.53, 72–77 (1994). [DOI] [PubMed] [Google Scholar]
24.Kubota, R., Kawanishi, T., Matsubara, H., Manns, A. & Jacobson, S. Demonstration of human T lymphotropic virus type I (HTLV-I) tax-specific CD8 + lymphocytes directly in peripheral blood of HTLV-I-associated myelopathy/tropical spastic paraparesis patients by intracellular cytokine detection. J. Immunol.161, 482–488 (1998). [PubMed] [Google Scholar]
25.Sandoval, R. et al. TNF-alpha increases production of reactive oxygen species through Cdk5 activation in nociceptive neurons. Front. Physiol.9, 65 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Takahashi, M. et al. HTLV-1 tax oncoprotein stimulates ROS production and apoptosis in T cells by interacting with USP10. Blood122, 715–725 (2013). [DOI] [PubMed] [Google Scholar]
27.Snyder, N. A. & Silva, G. M. Deubiquitinating enzymes (DUBs): regulation, homeostasis, and oxidative stress response. J. Biol. Chem.297, 101077 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Katsuragi, Y., Ichimura, Y. & Komatsu, M. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J.282, 4672–4678 (2015). [DOI] [PubMed] [Google Scholar]
29.Duan, W. et al. Novel insights into neun: from neuronal marker to splicing regulator. Mol. Neurobiol.53, 1637–1647 (2016). [DOI] [PubMed] [Google Scholar]
30.Unal-Cevik, I., Kilinc, M., Gursoy-Ozdemir, Y., Gurer, G. & Dalkara, T. Loss of NeuN immunoreactivity after cerebral ischemia does not indicate neuronal cell loss: a cautionary note. Brain Res.1015, 169–174 (2004). [DOI] [PubMed] [Google Scholar]
31.Umehara, F. et al. Apoptosis of T lymphocytes in the spinal cord lesions in HTLV-I-associated myelopathy: a possible mechanism to control viral infection in the central nervous system. J. Neuropathol. Exp. Neurol.53, 617–624 (1994). [DOI] [PubMed] [Google Scholar]
32.Takahashi, M. et al. Dual regulatory roles of USP10 in Tau pathology and neuronal fate during alzheimer’s disease progression. Mol Cell. Biol2025, 1–24 (2025). [DOI] [PubMed]
33.Guise, A. J. et al. TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis. Cell. Rep.43, 113636 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
34.D’Amelio, M., Cavallucci, V. & Cecconi, F. Neuronal caspase-3 signaling: not only cell death. Cell. Death Differ.17, 1104–1114 (2010). [DOI] [PubMed] [Google Scholar]
35.Mukherjee, A. & Williams, D. W. More alive than dead: non-apoptotic roles for caspases in neuronal development, plasticity and disease. Cell. Death Differ.24, 1411–1421 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Meystre, J. et al. Cell density quantification of high resolution Nissl images of the juvenile rat brain. Front. Neuroanat.18, 1463632 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material 1^{(85.9KB, pdf)}

Supplementary Material 2^{(252.7KB, pdf)}

Data Availability Statement

The dataset supporting the conclusions of this article is included within the article and its additional file.

[CR1] 1.Gessain, A. & Cassar, O. Epidemiological aspects and world distribution of HTLV-1 infection. Front. Microbiol.3, 388 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR2] 2.Uchiyama, T., Yodoi, J., Sagawa, K., Takatsuki, K. & Uchino, H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood50, 481–492 (1977). [PubMed] [Google Scholar]

[CR3] 3.Gessain, A. et al. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet2, 407–410 (1985). [DOI] [PubMed] [Google Scholar]

[CR4] 4.Osame, M. et al. HTLV-I associated myelopathy, a new clinical entity. Lancet1, 1031–1032 (1986). [DOI] [PubMed] [Google Scholar]

[CR5] 5.Osame, M. et al. Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemialike cells. Ann. Neurol.21, 117–122 (1987). [DOI] [PubMed] [Google Scholar]

[CR6] 6.Umehara, F. et al. Immunocytochemical analysis of the cellular infiltrate in the spinal cord lesions in HTLV-I-associated myelopathy. J. Neuropathol. Exp. Neurol.52, 424–430 (1993). [DOI] [PubMed] [Google Scholar]

[CR7] 7.Matsuura, E., Kubota, R., Tanaka, Y., Takashima, H. & Izumo, S. Visualization of HTLV-1-specific cytotoxic T lymphocytes in the spinal cords of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. J. Neuropathol. Exp. Neurol.74, 2–14 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR8] 8.Moritoyo, T. et al. Human T-lymphotropic virus type I-associated myelopathy and tax gene expression in CD4 + T lymphocytes. Ann. Neurol.40, 84–90 (1996). [DOI] [PubMed] [Google Scholar]

[CR9] 9.Matsuoka, E. et al. Perivascular T cells are infected with HTLV-I in the spinal cord lesions with HTLV-I-associated myelopathy/tropical spastic paraparesis: double staining of immunohistochemistry and polymerase chain reaction in situ hybridization. Acta Neuropathol.96, 340–346 (1998). [DOI] [PubMed] [Google Scholar]

[CR10] 10.Ijichi, S. et al. An autoaggressive process against bystander tissues in HTLV-I-infected individuals: a possible pathomechanism of HAM/TSP. Med. Hypotheses. 41, 542–547 (1993). [DOI] [PubMed] [Google Scholar]

[CR11] 11.Nozuma, S., Kubota, R. & Jacobson, S. Human T-lymphotropic virus type 1 (HTLV-1) and cellular immune response in HTLV-1-associated myelopathy/tropical spastic paraparesis. J. Neurovirol.26, 652–663 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR12] 12.Bhattacharya, U., Neizer-Ashun, F., Mukherjee, P. & Bhattacharya, R. When the chains do not break: the role of USP10 in physiology and pathology. Cell. Death Dis.11, 1033 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR13] 13.Jia, R. & Bonifacino, J. S. The ubiquitin isopeptidase USP10 deubiquitinates LC3B to increase LC3B levels and autophagic activity. J. Biol. Chem.296, 100405 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR14] 14.Ye, Z., Chen, J., Huang, P., Xuan, Z. & Zheng, S. Ubiquitin-specific peptidase 10, a deubiquitinating enzyme: assessing its role in tumor prognosis and immune response. Front. Oncol.12, 990195 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR15] 15.Sango, J. et al. USP10 inhibits the dopamine-induced reactive oxygen species-dependent apoptosis of neuronal cells by stimulating the antioxidant Nrf2 activity. J. Biol. Chem.298, 101448 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR16] 16.Wang, L., Wu, D. & Xu, Z. USP10 protects against cerebral ischemia injury by suppressing inflammation and apoptosis through the Inhibition of TAK1 signaling. Biochem. Biophys. Res. Commun.516, 1272–1278 (2019). [DOI] [PubMed] [Google Scholar]

[CR17] 17.Alegre, F. et al. Role of p62/SQSTM1 beyond autophagy: a lesson learned from drug-induced toxicity in vitro. Br. J. Pharmacol.175, 440–455 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR18] 18.Takahashi, M. et al. USP10 is a driver of ubiquitinated protein aggregation and aggresome formation to inhibit apoptosis. iScience9, 433–450 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR19] 19.Xie, C., Gao, X., Liu, G., Tang, H. & Li, C. USP10 is a potential mediator for vagus nerve stimulation to alleviate neuroinflammation in ischaemic stroke by inhibiting NF-kappaB signalling pathway. Front. Immunol.14, 1130697 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR20] 20.Tendler, C. L. et al. Cytokine induction in HTLV-I associated myelopathy and adult T-cell leukemia: alternate molecular mechanisms underlying retroviral pathogenesis. J. Cell. Biochem.46, 302–311 (1991). [DOI] [PubMed] [Google Scholar]

[CR21] 21.Gong, Y. et al. Inhibition of the NKCC1/NF-kappaB signaling pathway decreases inflammation and improves brain edema and nerve cell apoptosis in an SBI rat model. Front. Mol. Neurosci.14, 641993 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR22] 22.Ye, L. et al. IL-1beta and TNF-alpha induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J. Neurochem.125, 897–908 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR23] 23.Umehara, F. et al. Cytokine expression in the spinal cord lesions in HTLV-I-associated myelopathy. J. Neuropathol. Exp. Neurol.53, 72–77 (1994). [DOI] [PubMed] [Google Scholar]

[CR24] 24.Kubota, R., Kawanishi, T., Matsubara, H., Manns, A. & Jacobson, S. Demonstration of human T lymphotropic virus type I (HTLV-I) tax-specific CD8 + lymphocytes directly in peripheral blood of HTLV-I-associated myelopathy/tropical spastic paraparesis patients by intracellular cytokine detection. J. Immunol.161, 482–488 (1998). [PubMed] [Google Scholar]

[CR25] 25.Sandoval, R. et al. TNF-alpha increases production of reactive oxygen species through Cdk5 activation in nociceptive neurons. Front. Physiol.9, 65 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR26] 26.Takahashi, M. et al. HTLV-1 tax oncoprotein stimulates ROS production and apoptosis in T cells by interacting with USP10. Blood122, 715–725 (2013). [DOI] [PubMed] [Google Scholar]

[CR27] 27.Snyder, N. A. & Silva, G. M. Deubiquitinating enzymes (DUBs): regulation, homeostasis, and oxidative stress response. J. Biol. Chem.297, 101077 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR28] 28.Katsuragi, Y., Ichimura, Y. & Komatsu, M. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J.282, 4672–4678 (2015). [DOI] [PubMed] [Google Scholar]

[CR29] 29.Duan, W. et al. Novel insights into neun: from neuronal marker to splicing regulator. Mol. Neurobiol.53, 1637–1647 (2016). [DOI] [PubMed] [Google Scholar]

[CR30] 30.Unal-Cevik, I., Kilinc, M., Gursoy-Ozdemir, Y., Gurer, G. & Dalkara, T. Loss of NeuN immunoreactivity after cerebral ischemia does not indicate neuronal cell loss: a cautionary note. Brain Res.1015, 169–174 (2004). [DOI] [PubMed] [Google Scholar]

[CR31] 31.Umehara, F. et al. Apoptosis of T lymphocytes in the spinal cord lesions in HTLV-I-associated myelopathy: a possible mechanism to control viral infection in the central nervous system. J. Neuropathol. Exp. Neurol.53, 617–624 (1994). [DOI] [PubMed] [Google Scholar]

[CR32] 32.Takahashi, M. et al. Dual regulatory roles of USP10 in Tau pathology and neuronal fate during alzheimer’s disease progression. Mol Cell. Biol2025, 1–24 (2025). [DOI] [PubMed]

[CR33] 33.Guise, A. J. et al. TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis. Cell. Rep.43, 113636 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR34] 34.D’Amelio, M., Cavallucci, V. & Cecconi, F. Neuronal caspase-3 signaling: not only cell death. Cell. Death Differ.17, 1104–1114 (2010). [DOI] [PubMed] [Google Scholar]

[CR35] 35.Mukherjee, A. & Williams, D. W. More alive than dead: non-apoptotic roles for caspases in neuronal development, plasticity and disease. Cell. Death Differ.24, 1411–1421 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR36] 36.Meystre, J. et al. Cell density quantification of high resolution Nissl images of the juvenile rat brain. Front. Neuroanat.18, 1463632 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Downregulation of the deubiquitinating enzyme USP10 correlates with neuronal apoptosis in HTLV-1-associated myelopathy

Shiho Arishima

Masahiko Takahashi

Mika Dozono

Takashi Yoshida

Satoshi Nozuma

Hiroshi Takashima

Masahiro Fujii

Ryuji Kubota

Abstract

Supplementary Information

Introduction

Results

USP10 expression in the spinal cords of HAM patients

Fig. 1.

Table 1.

Neuronal apoptosis in the spinal cords of HAM patients

Fig. 2.

Neuronal cell density in the spinal cords of HAM patients

Fig. 3.

p62 expression in the spinal cords of HAM patients

Fig. 4.

Correlation analyses among USP10 expression, neuronal apoptosis, p62 expression, and neuronal cell density in HAM spinal cords

Fig. 5.

Discussion

Table 2.

Materials and methods

Subjects

Immunohistochemical analysis

Evaluation of staining results

TUNEL assay

Statistics

Supplementary Information

Author contributions

Funding

Data availability

Competing interests

Ethics approval and consent to participate

Footnotes

Contributor Information

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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