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. 2023 Nov 8;19(7):1463–1472. doi: 10.4103/1673-5374.387967

α-Synuclein pathology from the body to the brain: so many seeds so close to the central soil

Yunying Yang 1, Zhentao Zhang 1,2,*
PMCID: PMC10883481  PMID: 38051888

Abstract

α-Synuclein is a protein that mainly exists in the presynaptic terminals. Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases, including Parkinson's disease. Aggregated and highly phosphorylated α-synuclein constitutes the main component of Lewy bodies in the brain, the pathological hallmark of Parkinson's disease. For decades, much attention has been focused on the accumulation of α-synuclein in the brain parenchyma rather than considering Parkinson's disease as a systemic disease. Recent evidence demonstrates that, at least in some patients, the initial α-synuclein pathology originates in the peripheral organs and spreads to the brain. Injection of α-synuclein preformed fibrils into the gastrointestinal tract triggers the gut-to-brain propagation of α-synuclein pathology. However, whether α-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous α-synuclein preformed fibrils or pathological α-synuclein leakage from the central nervous system remains under investigation. In this review, we aimed to summarize the role of peripheral α-synuclein pathology in the pathogenesis of Parkinson's disease. We also discuss the pathways by which α-synuclein pathology spreads from the body to the brain.

Key Words: aggregation, autonomic nervous system, barrier receptors, body fluid circulation, in situ generation, Parkinson's disease, phosphorylation, propagation, synucleinopathies, α-synuclein, α-synuclein fibrils

Introduction

α-Synuclein: genes, protein characteristics, and protein behaviors

α-Synuclein (α-Syn) is encoded by the SNCA gene, which is located on the long arm of chromosome 4 (Mizuno et al., 1999). Mutations in the SNCA gene, including A53T, A30P, E46K, G51D, H50Q, duplication, triplication, multiplication, etc., result in their carriers being susceptible to α-Syn pathology, among which A53T carriers exhibit the strongest tendency to form α-Syn pathology in the brain (Ikeuchi et al., 2008; Byers et al., 2011; Porcari et al., 2015; Zhang et al., 2019; Boyer et al., 2020; Joshi et al., 2023; Lau et al., 2023). Compared to healthy controls, A53T carriers had lower levels of serum α-Syn, indicating dysregulated homeostasis of α-Syn caused by SNCA mutation (Emmanouilidou et al., 2020). A53T carriers also show early and persistent accumulation of phosphorylated α-Syn in the enteric nervous system as well as an altered profile of peripheral immune cells, suggesting the potential influence of SNCA mutation on peripheral α-Syn pathology (Bencsik et al., 2014; Idova et al., 2021).

α-Syn has three major domains: N-terminal domain [amino acid (a.a.) 1–60], central domain (a.a. 61–95), and C-terminal domain (a.a. 96–140) (Wang et al., 2019). The N-terminal domain is highly hydrophobic, containing a consensus sequence (a.a. sequence: KTKEGV) consisting of seven imperfect repeats (a.a. 7–87). Deletion of the 13 residues in the N-terminus accelerates the fibrillization of α-Syn (McGlinchey et al., 2021). The central domain is called the non-amyloid-β component, which is indispensable for α-Syn aggregation (Xu et al., 2016). The C-terminus is negatively charged and flexible, which resists aggregation of the protein (Kumari et al., 2021). In vitro and intracellular nuclear magnetic resonance evidence showed that in the normal cellular environment, α-Syn appears as monomeric and disordered (Theillet et al., 2016). Other evidence showed that α-Syn can also form helically folded tetramers that resist aggregation (Selkoe et al., 2014). The aggregation propensity of α-Syn is regulated by the extent of N-terminus exposure (Stephens et al., 2020).

As a synaptic protein, α-Syn regulates synaptic vesicle trafficking and neurotransmitter release. The exact physiological behaviors of α-Syn need to be further investigated (Burré et al., 2010; Butler et al., 2015). The accumulation and hyperphosphorylation of α-Syn play a pivotal role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies. The already aggregated pathological α-Syn acts as “seeds” to template the aggregation of the remaining soluble counterparts. This abnormal behavior endows it with the characteristics of prion-like proteins (Fink, 2006; Peng et al., 2018; Lau et al., 2020). Aggregated α-Syn is also highly phosphorylated in the brain in PD. The phosphorylation of α-Syn is believed to be mediated by protein kinases including casein kinase 2 and death-associated protein kinase 1. Other kinases may also contribute to the phosphorylation of α-Syn (Fujiwara et al., 2002; Su et al., 2019; Hu et al., 2020; Yu et al., 2022a). The processes of α-Syn aggregation and phosphorylation interact with each other in an ambiguous order of occurrence. Phosphorylation of α-Syn at Ser129, the most commonly observed phosphorylation site, promotes the formation of fibrils, which reversely act on the “soil” of α-Syn monomers and subsequently induce the formation of α-Syn-enriched insoluble inclusions in the cytoplasm of brain cells (Chen and Feany, 2005; Helwig et al., 2016; Froula et al., 2019; Leitão et al., 2021; Yang et al., 2021; Ghanem et al., 2022). Intracerebral injection of α-Syn preformed fibrils (α-Syn PFFs), an artificial analog of α-Syn fibrils, into wild-type mice gave rise to typical α-Syn pathology in the brain, along with loss of dopaminergic neurons, blood-brain barrier (BBB) dysfunction, glial activation, neuroinflammation, and PD-like behavioral deficits (Luk et al., 2012b; Kim et al., 2018; Yun et al., 2018; Bieri et al., 2019; Ding et al., 2021; Butler et al., 2022). Pathological α-Syn can be detected not only in the brain but also in other peripheral organs, body fluids, and autonomic nerves, indicating the flowability and cell-to-cell transmission of pathological α-Syn (Mollenhauer et al., 2011; Wood, 2016; Iranzo et al., 2021; Sharabi et al., 2021; Lobanova et al., 2022; Poggiolini et al., 2022).

Synucleinopathies

PD

Synucleinopathies cover a series of neurodegenerative diseases with α-Syn aggregates, including Lewy body (LB) diseases [including PD, PD with dementia (PDD), and dementia with LBs (DLB)] and multiple system atrophy (MSA) (Koga et al., 2021). PD is the second most common neurodegenerative disease and one of the most studied synucleinopathies, with growing prevalence, disability, and lethality over the years (Pagonabarraga et al., 2015; Bloem et al., 2021). The pathological hallmark of PD is the loss of dopaminergic neurons in the substantia nigra (SN) and the formation of Lewy neurites and LBs consisting mainly of aggregated hyperphosphorylated α-Syn (Spillantini et al., 1997; Yang et al., 2022). Both genetic and environmental factors contribute to the onset of PD (Goldsmith et al., 1997; Polymeropoulos et al., 1997; Menegon et al., 1998; Healy et al., 2008; Tysnes and Storstein, 2017; Blauwendraat et al., 2020). To date, over 8.5 million people have been affected worldwide by PD (Rocca, 2018; GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators, 2019; World Health Organization, 2022).

PD is characterized by both motor and non-motor symptoms (Alarcón et al., 2023). The motor symptoms of PD include static tremor, rigidity, bradykinesia, and changes in posture and gait, resulting from hyperactivity of the acetylcholinergic system relative to deficiency of dopamine (de Bie et al., 1999; Tolosa et al., 2006; Li et al., 2012; Bai and Li, 2021; Nawaz et al., 2022). The non-motor features of PD include sleep disorders, constipation, dysfunction of autonomic nerves, cognitive decline, and depression, which usually occur as atypical symptoms in early stages of PD (Cooper et al., 1992; Wakabayashi and Takahashi, 1997; Williams and Lees, 2005; Camilleri et al., 2022; De Cock et al., 2022; Zhang et al., 2022b).

Other synucleinopathies

In addition to PD, LB diseases also include PDD and DLB. LB diseases share common neuropathological changes: Parkinsonism, cognitive decline, hallucinations, sleep disorders, and fluctuating attention (Donaghy et al., 2018). PD pathology is more confined to the brainstem and limbic regions, while PDD and DLB pathology is more diffuse in the neocortex (Colosimo et al., 2003). Huang et al. (2021) reported that in PDD, α-Syn predominantly causes dementia, while in DLB cases, the cooperation of α-Syn and amyloid β exert the effect. It has been reported that the α-Syn level in the cerebrospinal fluid (CSF) of DLB patients is higher than that of PDD patients (Bougea et al., 2018, 2020). MSA has two major clinical subtypes, MSA-C (MSA with predominant cerebellar ataxia) and MSA-P (MSA with predominant Parkinsonism) (Kalia et al., 2015; Guo et al., 2023). MSA is characterized by the presence of α-Syn-positive glial cytoplasmic inclusions (Papp and Lantos, 1994; Huang et al., 2008; Teil et al., 2022). α-Syn-positive inclusions also invade neurons in MSA, resulting in neuronal cytoplasmic inclusions (Wakabayashi et al., 1998; Hass et al., 2021). The direct correlation between neuronal cytoplasmic inclusions and glial cytoplasmic inclusions remains largely unknown. The density of accumulative glial cytoplasmic inclusions is positively correlated with the clinical manifestations of MSA, typical of which is early and severe autonomic failure, presenting as urinary urge incontinence or retention and orthostatic hypotension (Ozawa et al., 2004; Swaminath et al., 2010; Squair et al., 2022). α-Syn aggregates were also found in the urinary system and correlated with urinary symptoms in MSA (Peelaerts et al., 2023).

‘Brain-first’ and ‘body-first’ transmission mode of α-Syn pathology

The accumulation and propagation patterns of α-Syn have been extensively studied in synucleinopathies. Pathological analysis performed by Braak et al. (2003) showed that α-Syn pathology initially occurs in the dorsal motor nucleus of the glossopharyngeal nerve and the anterior olfactory nucleus, medulla, pontine tegmentum, and midbrain, and finally invades the neocortex, leading to the hypothesis that α-Syn pathology may spread through the nervous system. In some patients with prodromal symptoms of PD, 123I-metaiodobenzylguanidine scintigraphy showed fully developed pathology in the peripheral autonomic nervous system and the locus coeruleus, equal to that in diagnosed PD cases. This peripheral dysfunction of the autonomic nervous system supports that PD pathology initiates from peripheral autonomic nerves and then spreads rostrally to the brainstem in some cases (Knudsen et al., 2018). In addition, using a multimodal imaging method, Jacob Horsager and colleagues further validated the existence of both subtypes of PD pathology: brain-first parkinsonism (pathology found sequentially in the amygdala, SN, locus coeruleus, dorsal motor nucleus, and heart) and body-first parkinsonism (pathology found sequentially in the intestine, heart, dorsal motor nucleus, locus coeruleus, and SN) (Horsager et al., 2020). However, the mechanisms underlying the propagation of α-Syn throughout the body remain under investigation.

In this review, we aimed to summarize the existence and production of α-Syn pathology in the peripheral organs and their possible role as a source of peripheral and central α-Syn pathology. Furthermore, the propagation modes of peripheral α-Syn pathology, including the autonomic nerve pathway and body fluid pathway, and the fibrillization microenvironment in which these two pathways are conducive to the formation of peripheral α-Syn pathology were discussed to provide a peripheral and systemic view of α-Syn pathology as a supplement for recognizing the pathogenesis of synucleinopathies.

Search Strategy

Articles published from the year 1992 to 2023 included in this narrative review were screened and selected from the PubMed database. The search keywords included, but were not limited to, Parkinson's disease (and) α-synuclein (and) synucleinopathy; peripheral α-synuclein; α-synuclein (and) brain; α-synuclein (and) heart; α-synuclein (and) liver; α-synuclein (and) spleen; α-synuclein (and) spleen; α-synuclein (and) intestinal; α-synuclein (and) skin; α-synuclein (and) glands; α-synuclein (and) autonomic nerve; α-synuclein (and) blood. The articles that did not correspond to peripheral α-Syn pathology were excluded.

The Source of Peripheral α-Synuclein Pathology

Solid viscera and glands

α-Syn is abundantly expressed in the central nervous system (Agliardi et al., 2022; Alam et al., 2022a; Pena-DIaz and Ventura, 2022). Thus, most previous studies have focused on α-Syn pathology in the brain (Luk et al., 2012a; Masuda-Suzukake et al., 2013). Pathological α-Syn aggregates can also be detected in peripheral organs, such as the liver and heart, which have a high distribution density of nerves and blood vessels (Navarro-Otano et al., 2013; Javanshiri et al., 2022). Studies have indicated that the liver may help to clear pathological α-Syn, while overexpression of α-Syn in the perivascular nerve fiber lowered norepinephrin-induced contraction of the mouse aorta (Marrachelli et al., 2010; Reyes et al., 2021). In these cases, pathological α-Syn may come from brain-originated α-Syn leakage across the BBB and blood-CSF circulation, which communicates with the autonomic nerve system, or possibly from in situ generation within these solid viscera. The neuroendocrine organs and glands are also affected by α-Syn pathology, which is related to symptoms such as depression in PD. For example, phosphorylated α-Syn can be detected in the posterior pituitary lobe and salivary glands (Homma et al., 2012). Therefore, a biopsy of the salivary glands may facilitate the early diagnosis of PD (Del Tredici et al., 2010; Gelpi et al., 2014; Vilas et al., 2016). According to these findings, the solid viscera and glands can be a potential source of peripheral α-Syn pathology.

Gastrointestinal tract

In the early stage of PD, intestinal inflammation induces dysregulation of the gut microbiota. Gut microbiota dysbiosis is closely related to motor phenotypes observed in PD (Dodiya et al., 2020). The gut microbiota and their secretions may directly promote the aggregation of α-Syn. It is possible that the formation of α-Syn pathology in the gut may alter the gut microbiota (Scheperjans et al., 2015; Sampson et al., 2016, 2020; Wang et al., 2021a). The intestinal bacteria Enterobacteriaceae can secrete the functional amyloid protein major fimbrial subunit of thin curled fimbriae, which is believed to contribute to α-Syn aggregation. Inhibiting the expression of the intestinal major fimbrial subunit of thin curled fimbriae alleviates α-Syn pathology (Sampson et al., 2020; Wang et al., 2021a). Antibiotic-treated mice display less α-Syn pathology; in contrast, recolonization of the microbiota will aggravate α-Syn pathology (Sampson et al., 2016). This is consistent with the observation that the density of Enterobacteriaceae is positively associated with the severity of postural instability and gait difficulty in PD patients (Scheperjans et al., 2015). α-Syn pathology observed in other parts of the digestive tract, such as the esophagus, is also correlated with disease progression (Tanei et al., 2021). Hits from these digestive tract pathological α-Syn and the pathological reactions it causes together contribute to prodromal enteric nervous system dysfunctions, which manifest clinically as hydrostomia, dysphagia, gastroparesis, and constipation (Manfredsson et al., 2018). These observations support the presence of pathological α-Syn in the gastrointestinal tract and its potential in generating in situ α-Syn pathology.

Skin and mucosal tissues

PD is genetically associated with various skin diseases such as melanoma, sweating disorders, dermatophytosis, and seborrheic dermatitis (Dube et al., 2020; Scott et al., 2021). Antemortem skin biopsies conducted by Wang et al. (2020) revealed the existence of pathological α-Syn deposits with seeding activity within the skin among PD and other synucleinopathy cases. Phosphorylated, oligomeric, and aggregated forms of α-Syn are also commonly seen in various skin cells, such as cutaneous nerve cells, indicating communication of PD pathology between the cutaneous nerves and the central nervous system (Spehlmann, 1975; Doppler et al., 2017; Israel and Asch, 2020; Mazzetti et al., 2020; Marano et al., 2022; Nolano et al., 2022; Park et al., 2022). Therefore, detection of pathological α-Syn in the skin and olfactory mucosa is used to diagnose prodromal PD symptoms (Doppler et al., 2022). These results revealed the possibility of pathological α-Syn in the skin and mucosal tissues as a source of peripheral synucleinopathy.

Transmission Pathways of α-Synuclein Pathology from Peripheral Organs to the Brain

The autonomic nerve pathway

Pathological α-Syn accumulates in peripheral tissues many years before the appearance of motor symptoms in synucleinopathies (Palma et al., 2018; Yamada et al., 2020; Camacho et al., 2021; Van Den Berge et al., 2021). Braak et al. (2003) hypothesized that synucleinopathic lesions originate from the peripheral nervous system and spread via the autonomic nerves to the dorsal motor nucleus of the vagus nerve and to the cerebral cortex. Kim et al. (2019) injected α-Syn fibrils into the duodenal and pyloric muscularis layers, which are densely innervated by the vagus nerve, and detected α-Syn lesions in the brain. As expected, pathological changes were first found in the dorsal motor nucleus and then in the caudal portions of the hindbrain. Vagotomy of the autonomic nerve pathway almost completely blocked the propagation from the gastrointestinal tract to the brain (Kim et al., 2019; Chen et al., 2021). Similarly, pathological α-Syn is also enriched in the appendix, and appendectomy may delay PD onset (Killinger et al., 2018). The widespread distribution of α-Syn deposits in autonomic nerves and their upward communication with the central nervous system provide solid evidence supporting the hypothesis that α-Syn may initiate from peripheral tissues. However, considering that α-Syn pathology is predominant in the brain rather than in other tissues, peripheral α-Syn deposits may originate from central nervous system leakage rather than in situ generation. Under in vivo conditions, aggregated α-Syn in the brain may spread to the autonomic nerves, which is then transferred to autonomic nerve-enriched peripheral tissues via mechanisms including macromolecule transport, endocytosis, exocytosis, or neuroendocrine processes (Li et al., 2022). Pathological α-Syn may be further processed in the peripheral organ environment or retained in situ for a long time, thus accounting for nonmotor autonomic symptoms, including hydrostomia, dysphagia, gastroparesis, and constipation (Barboza et al., 2015). Conversely, peripheral pathological α-Syn also crosses the BBB and is transported to the central nervous system, becoming part of the sources leading to central α-Syn pathology. This dual transmission forms a vicious circle between central and peripheral α-Syn pathology (Arotcarena et al., 2020).

The body fluid circulation pathway

The autonomic nerve pathway that pathological α-Syn relies on to propagate between the central nervous system and enteric nervous system could result in PD being considered as a systematic disease. However, the autonomic nervous system is not the only pathway that contributes to the flowability of pathological α-Syn. Early in 2006, El-Agnaf et al. (2006) validated the existence of pathological α-Syn in the CSF. High levels of α-Syn in the CSF are associated with PD symptoms and progression (Mollenhauer et al., 2013; Wurster et al., 2022; Coutinho et al., 2023). In addition to the CSF, pathological α-Syn has also been detected in other bodily fluids, including the saliva, lymph, and blood (Sergeyeva et al., 2011; Kluge et al., 2022; Luan et al., 2022). For instance, plasma α-Syn levels are also reported to be related to some signs of PD (Malec-Litwinowicz et al., 2018). Similar to the autonomic nervous system pathway, the circulation of intracellular bodily fluids, including the plasma, CSF, interstitial fluids, and lymph, also results in the transmission of pathological α-Syn between the brain and the peripheral organs (Kim et al., 2012; Matsui and Matsui, 2017; Bartl et al., 2022).

α-Syn expression in the blood is most abundant in red blood cells (Liu et al., 2021). Erythrocytic α-Syn is expressed at both the mRNA and protein levels throughout the lifetime of red blood cells; therefore, α-Syn possibly influences the hemopoietic system (Nakai et al., 2007). It has been reported that erythrocytic α-Syn levels are linked to the occurrence of constipation, a common autonomic symptom of PD (Martínez-Rodríguez and Rey-Buitrago, 2020). In addition, the level of hemoglobin-binding α-Syn is elevated in patients with α-Syn pathology, which is also reported to be related to some sympathetic symptoms observed in PD (Umehara et al., 2020; Zhang et al., 2022a). In the brain parenchyma, α-Syn is located on the presynaptic membrane, showing high proximity in spatial position with membrane lipid rafts, which may participate in its transmission among brain cells (Perissinotto et al., 2020); in contrast, α-Syn in the blood binds to lipoproteins, thus influencing lipid transport (Emamzadeh and Allsop, 2017; Sinclair et al., 2021).

Phosphorylation is a widely studied post-translational modification of α-Syn that promotes α-Syn aggregation. The levels of phosphorylated α-Syn both inside red blood cells and on the erythrocytic membranes of patients with PD are much higher than those of healthy controls (Tian et al., 2019). Moreover, the level of oligomeric α-Syn in erythrocytes was increased in the early stage of PD (Liu et al., 2022). There is evidence that higher erythrocytic oligomeric α-Syn levels predict accelerated disease progression (Yu et al., 2022b). These blood-oriented phosphorylated α-Syn proteins resist digestion by protein kinase K, similar to α-Syn inclusions extracted from the brain, and are capable of binding phospholipids and plasma proteins (Abd-Elhadi et al., 2015; Iyer et al., 2016). In addition to being transported by plasma proteins, these pathological phosphorylated α-Syn proteins may also be transmitted from the blood to the brain by erythrocytic extracellular vesicles via membrane fusion with the BBB (Matsumoto et al., 2017). Additionally, phosphorylation is not the only post-translational modification found in erythrocytic α-Syn; it has been reported that the lysine residues in erythrocytic α-Syn can be modified by acetylation, glycation, ubiquitination, SUMOylation, and even nitration and acylation, similar to that found in the brain of PD patients. In conclusion, this data supports that erythrocytic α-Syn may play a role in the peripheral formation and propagation of synucleinopathies (Amagai et al., 2023).

On the one hand, the abovementioned erythrocytic normal and pathological α-Syn may originate from the leakage of brain-oriented pathological α-Syn through the BBB or blood-CSF circulation. Many experiments have validated this brain-to-blood propagation. When radio-labeled α-Syn fibrils are injected into certain brain regions or directly into the lateral ventricle, they can be detected in the CSF, peripheral blood, and even in some peripheral tissues (Sui et al., 2014). On the other hand, from the peripheral perspective, other peripheral administration routes of α-Syn PFFs, including oral, intranasal, intraperitoneal, and intramuscular administration, as well as tail vein injection, can also lead to brain α-Syn pathology similar to that induced by intracerebral injection of α-Syn PFFs, proving the existence of α-Syn propagation between the blood and brain through the circulation of bodily fluids (Ayers et al., 2017; Earls et al., 2019; Macdonald et al., 2021; Masuda-Suzukake et al., 2021; Awa et al., 2022).

Multiple Factors Mediate the Propagation of Peripheral α-Synuclein Pathology to the Brain

BBB receptors

The BBB is the main barrier and the most pivotal structural basis blocking the entry of peripheral pathological α-Syn into the brain. The BBB is altered in the brain of PD patients, which results from hits of pathological α-Syn (Dohgu et al., 2019; Tsunemi et al., 2020; Xia et al., 2021; Huang et al., 2022a). Brain microvascular endothelial cells, astrocytes, and pericytes are the main components of the BBB and blood-CSF barrier (Campisi et al., 2018). Peripheral pathological α-Syn is most likely transported across the BBB via interaction with receptors on these cells and extracellular vesicles. These receptors can be divided into three categories according to their affinity to pathological α-Syn: transporters mediating α-Syn transmission by direct binding, facilitators regulating vesicle trafficking of pathological α-Syn, and receptors affecting BBB permeability conducive to α-Syn propagation (Table 1; Calderón-Garcidueñas et al., 2008; Kanekiyo et al., 2011; Jangula and Murphy, 2013; Chen et al., 2015; Mao et al., 2016; Masaracchia et al., 2018; Phillips et al., 2018; Bae and Lee, 2020; Rauch et al., 2020; Emmenegger et al., 2021; Gasca-Salas et al., 2021; Gu et al., 2021; Kim et al., 2021; Pediaditakis et al., 2021; Streubel-Gallasch et al., 2021; Wang et al., 2021b, c; Zhang et al., 2021, 2023a, c; Alam et al., 2022b; Chen et al., 2022; Feng et al., 2022; Huang et al., 2022a; Lan et al., 2022; Prieto Huarcaya et al., 2022; Roshanbin et al., 2022; Ruan et al., 2022; Salman et al., 2022; Shin et al., 2022; Vellingiri et al., 2022). Direct binding was found between α-Syn fibrils and lymphocyte-activation gene 3, as well as amyloid precursor-like protein 1, which are widely expressed in blood, immune, and endothelial cells, thus mediating the transmission of α-Syn fibrils (Mao et al., 2016; Zhang et al., 2021). The second category includes astrocytic vascular endothelial growth factor A (VEGFA), low-density lipoprotein receptor-related protein 1, Ras-related in brain 7 (Rab7), and leucine-rich repeat kinase 2 (LRRK2), which are reported to regulate vesicle trafficking of pathological α-Syn. Blocking astrocyte VEGFA signaling in the in vitro BBB model effectively protects the barrier against the harmful effects of oligomeric α-Syn, while dysregulation of Rab7 signaling and LRRK2 signaling causes abortive clearance of pathological α-Syn, leading to α-Syn accumulation and propagation (Bae and Lee, 2020; Wang et al., 2021b; Alam et al., 2022b; Chen et al., 2022; Lan et al., 2022). When treating in vitro models of the BBB with α-Syn fibrils, a series of targets, including lipoprotein receptor-related protein 1 and LRRK2, have been proven to undergo alterations (Pediaditakis et al., 2021). Physical and environmental hits, such as ultrasound, air pollution, heavy metals, and a ketogenic diet, and chemical factors, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, lipopolysaccharide, cerebrolysin, and tissue plasminogen activator, are also reported to affect other BBB receptors, such as aquaporin 4, thus enhancing BBB permeability and contributing to the entry of pathological α-Syn into the brain (Calderón-Garcidueñas et al., 2008; Jangula and Murphy, 2013; Chen et al., 2015; Phillips et al., 2018; Gasca-Salas et al., 2021; Wang et al., 2021c; Feng et al., 2022; Ruan et al., 2022; Salman et al., 2022; Vellingiri et al., 2022).

Table 1.

BBB receptors interacting with α-Syn and α-Syn fibrils

Receptor name Interaction type with α-Syn Effect on α-Syn transportation
LAG3 Direct binding Transmission
APLP1
TLR2 Direct interaction
LRP1 Indirect interaction Vesicle trafficking, BBB permeability
Changed gene expression by α-Syn monomer
HSPG Indirect interaction, synergies with LRP1 Vesicle trafficking
Rab7 Indirect interaction
VEGFA
LRRK2 Indirect interaction
Changed gene expression by α-Syn monomer
IGF1R Indirect interaction Molecular shuttle
TfR
NEK BBB permeality
AQP4
Nurr1
M6PR
LRP2 Changed gene expression by α-Syn monomer BBB function
ABCB1
CLDN4 Changed gene expression by α-Syn fibril BBB function
CLDN9
CLDN1
SLC2A6
SLC16A6
GJA4
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Data were from studies Calderón-Garcidueñas et al., 2008; Kanekiyo et al., 2011; Jangula and Murphy, 2013; Chen et al., 2015; Mao et al., 2016; Masaracchia et al., 2018; Phillips et al., 2018; Bae and Lee, 2020; Rauch et al., 2020; Emmenegger et al., 2021; Gasca-Salas et al., 2021; Gu et al., 2021; Kim et al., 2021; Pediaditakis et al., 2021; Streubel-Gallasch et al., 2021; Wang et al., 2021b, c; Zhang et al., 2021, 2023a, c; Alam et al., 2022b; Chen et al., 2022; Feng et al., 2022; Huang et al., 2022a; Lan et al., 2022; Prieto Huarcaya et al., 2022; Roshanbin et al., 2022; Ruan et al., 2022; Salman et al., 2022; Shin et al., 2022; Vellingiri et al., 2022. ABCB1: Adenosine triphosphate-binding cassette subfamily B member 1; APLP1: amyloid precursor-like protein 1; AQP4: aquaporin-4; CLDN1: claudin-1; CLDN4: claudin-4; CLDN9: claudin-9; GJA4: gap junction protein alpha 4; SLC2A6: facilitated glucose transporter member 6; HSPG: heparan sulfate proteoglycan; IGF1R: insulin like growth factor 1 receptor; LRRK2: leucine-rich repeat kinase 2; LRP1: low-density lipoprotein receptor-related protein 1; LRP2: low-density lipoprotein receptor-related protein 2; LAG3: lymphocyte activation gene-3; M6PR: mannose-6-phosphate receptor; SLC16A6: monocarboxylate transporter 6; NEK: NimA related kinase; Nurr1: nuclear receptor-related factor 1; Rab7: Ras-related in brain 7; TLR2: Toll-like receptor 2; TfR: transferrin receptor-1; VEGFA: vascular endothelial growth factor A; α-Syn: α-synuclein.

However, it is controversial whether these interactions between pathological α-Syn and the receptors can actually aggravate the α-Syn pathology (Emmenegger et al., 2021; Gu et al., 2021). Often, these receptors have poor selectivity for α-Syn monomers, oligomers, and fibrils, as well as other aggregated proteins (Rauch et al., 2020). Even when confronted with the same protein fibrils, these receptors exhibit distinct binding affinities. α-Syn fibrils with post-translational modifications, such as phosphorylation at Ser129, are believed to have a higher bonding affinity with lymphocyte-activation gene 3 than pure fibrils (Zhang et al., 2023a). Except for poor selectivity, the widespread distribution and functional diversity of these receptors also limits their weight in regulating α-Syn propagation. For instance, lipoprotein receptor-related protein 1 is expressed on various cell types, including neurons, astrocytes, microglia, macrophages, fibroblasts, and smooth muscle cells, and cooperates with other endocytosis-related receptors, such as heparin sulfate proteoglycan, regulating cell-to-cell propagation of not only pathological α-Syn, but also pathological proteins typical of Alzheimer's disease (Kanekiyo et al., 2011). Likewise, in addition to promoting transmission, the LRRK2 and Rab7 pathways are also responsible for normal phagocytosis and clearance of pathological α-Syn (Masaracchia et al., 2018; Streubel-Gallasch et al., 2021). When peripheral pathological α-Syn is attached to a BBB receptor, clearance via lysosomal degradation and autophagy may occur first before it can enter the exocytosis pathway and then be transmitted among brain cells. It can be speculated that there is a receptor-mediated balance among endo- and exocytosis, and the clearance and propagation of pathological proteins, the disturbance of which ultimately leads to successful propagation of α-Syn pathology from the periphery to the central nervous system (Volpicelli-Daley et al., 2011; Rodrigues et al., 2022). Therefore, there is an urgent need to identify the key receptors with specificity that mediate the spreading of pathological α-Syn.

Properties of α-Syn fibrils

The main forms in which pathological α-Syn exists in PD brains are α-Syn oligomers, fibrils, and ribbons (Peelaerts et al., 2015; Rodriguez et al., 2015). The highly aggregated form, α-Syn ribbons, has the strongest seeding activity, while the oligomer and fibril are prone to cause cell toxicity and cell-to-cell transmission, respectively (Mahul-Mellier et al., 2015; Uemura et al., 2023). In different synucleinopathies, aggregated α-Syn possesses different properties. Both insoluble and soluble fractions of α-Syn-enriched brain extracts derived from MSA patients can induce the accumulation of normal α-Syn, while only insoluble fractions derived from patients with PD retain this seeding ability (Yamasaki et al., 2019; Van der Perren et al., 2020). Phosphorylation at Ser129 of α-Syn is another point distinguishing PD from other synucleinopathies (Sonustun et al., 2022). Approximately 90% of α-Syn in LBs in PD is hyperphosphorylated. Ubiquitination, acetylation, nitrification, palmitoylation, etc. also occupy a minority of modifications of α-Syn, influencing the properties of α-Syn fibrils (Sevcsik et al., 2011; Kunadt et al., 2015; Rott et al., 2017; Ho et al., 2023; Zhang et al., 2023b). Among these, phosphorylation of serine, ubiquitination, nitrification, glycation, etc. are believed to promote α-Syn aggregation and propagation (Table 2; Nonaka et al., 2005; Kim et al., 2006; Danielson et al., 2009; Lee et al., 2009; Waxman et al., 2010; Liu et al., 2011; Padmaraju et al., 2011; Izawa et al., 2012; Binolfi et al., 2016; Arawaka et al., 2017; Vicente Miranda et al., 2017; Zhang et al., 2017a, b; Wen et al., 2018; Barinova et al., 2019; Chavarría et al., 2019; Sanyal et al., 2019; Semenyuk et al., 2019; Zhao et al., 2020; Andersen et al., 2021; Dhakal et al., 2021; Hartlage-Rübsamen et al., 2021; Bell et al., 2022; Farzadfard et al., 2022; Jin et al., 2022; Kam et al., 2022; Panigrahi et al., 2023; Zhou et al., 2023). α-Syn can also be modified by other proteins, lipids, and small molecular compounds, which enhance or suppress its propagation or seeding activity (Masaracchia et al., 2018; Kim et al., 2021; Streubel-Gallasch et al., 2021). For example, asparagine endopeptidase cleaves α-Syn at N103, generating the α-Syn (1–103) fragment, which forms aggregates with higher pathogenicity, suggesting that fragmentation of α-Syn influences the properties of fibrils (Zhang et al., 2017b). Furthermore, chemical substances, such as homocysteine derivatives, can also modify α-Syn on the K80 residue, thus forming more toxic fibrils with higher seeding and propagation activity (Zhou et al., 2023). Most of these modified α-Syn proteins are more resistant to digestion by proteinases and are more likely to undergo fibrillation and aggregation; therefore, they are less easily engulfed and degraded by their host cells. In addition, they are more prone to undergo neuron–neuron, glia–neuron, and peripheral cell-brain cell propagation, forming the spreading mechanism of pathological α-Syn among the central nervous system and from the peripheral tissues to the central nervous system (Pluvinage et al., 2019; Yuan et al., 2022).

Table 2.

Posttranslational modifications that affect α-Syn properties

Modification Sites Modification effects
Phosphorylation Ser129 Promoting α-Syn aggregation
Ser87
Tyr39
Tyr136
Tyr125 Suppressing α-Syn aggregation
O-GlcNAcylation Thr72 Suppressing α-Syn aggregation
Ser87
Ubiquitination Lys6 Promoting α-Syn aggregation
Lys10
Lys12
Nitrification Tyr125 Promoting α-Syn aggregation
Tyr133
Tyr136
Tyr39
Glycation Not applicable Promoting α-Syn aggregation
Arginylation Glu83 Suppressing α-Syn aggregation
Acetylation Not applicable Postponing α-Syn aggregation
SUMOylation Not applicable Suppressing α-Syn aggregation
Nitroalkylation Not applicable Suppressing α-Syn aggregation
Adenylylation Not applicable Suppressing α-Syn aggregation
N-homocysteinylation (chemical modification) Lys80 Promoting α-Syn aggregation
Pyroglutamate (pGlu)79 (chemical modification) Gln79 Promoting α-Syn aggregation
Glyceraldehyde-3-phosphate (chemical modification) Not applicable Preventing α-Syn aggregation
4-Hydroxy-2-nonenal (chemical modification) His50 Promoting α-Syn aggregation
Dicarbonyl compounds (chemical modification) Not applicable Suppressing α-Syn aggregation
Tyrosine hydroxylase (chemical modification) Tyr136 Promoting α-Syn aggregation
Docosahexaenoic acid (chemical modification) Not applicable Promoting α-Syn aggregation
Asparagine endopeptidase (proteolysis) Asn103 Promoting α-Syn aggregation
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Data were from studies Nonaka et al., 2005; Kim et al., 2006; Danielson et al., 2009; Lee et al., 2009; Waxman et al., 2010; Liu et al., 2011; Padmaraju et al., 2011; Izawa et al., 2012; Binolfi et al., 2016; Arawaka et al., 2017; Vicente Miranda et al., 2017; Zhang et al., 2017a, b; Wen et al., 2018; Barinova et al., 2019; Chavarría et al., 2019; Sanyal et al., 2019; Semenyuk et al., 2019; Zhao et al., 2020; Andersen et al., 2021; Dhakal et al., 2021; Hartlage-Rübsamen et al., 2021; Bell et al., 2022; Farzadfard et al., 2022; Jin et al., 2022; Kam et al., 2022; Panigrahi et al., 2023; Zhou et al., 2023. α-Syn: α-Synuclein.

Microenvironment promotes the formation of peripheral α-Syn pathology

The aggregation and propagation of α-Syn requires a specific microenvironment. Thus, we propose that there is a fibrillization microenvironment (FME) composed of pathological α-Syn, the peripheral immune system, the erythrocytic intracellular environment, the autonomic nerve system, soluble and insoluble cytokines, ionic concentration, pH, temperature, hemodynamics, and the BBB (Figure 1). These elements together contribute to the focal enrichment of pathological α-Syn, isolating it from the liquid phase of the intracellular fluid and irreversibly forming agglutinative fibrils and ribbons (Huang et al., 2022b). For instance, dysfunction of ionic homeostasis, disturbance of BBB receptors, acidic pH, and dysregulation of phosphatases promote the formation and cell-to-cell transmission of α-Syn pathology (Bhak et al., 2014; Li et al., 2020, 2023a; Yu et al., 2021). From the peripheral view, the peripheral blood provides an immunity-centered FME that promotes the generation and propagation of peripheral pathological α-Syn. In addition, the adjacency in location between the blood and the autonomic nerves further enhances the effect of FME on the transmissibility of α-Syn pathology throughout the body.

Figure 1.

Figure 1

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Diagram of FME and the propagation mode of pathological α-Syn from peripheral organs to the brain.

The FME is composed of pathological α-Syn, the peripheral immune system, members of the BBB, the erythrocytic intracellular environment, and soluble and insoluble cytokines. (a) The erythrocytic intracellular environment contributes to the generation of pathological α-Syn. (b) Erythrocytic pathological α-Syn recruits B cells. (c) B cells secrete autoantibodies against α-Syn. (d) Autoantibodies of α-Syn promote clearance of erythrocytic pathological α-Syn. (e) A combination of α-Syn and its antibody leads to activation of the complement system. (f) Members of the complement system reversely aggravate α-Syn pathology. (g) T cells discriminate peptides of α-Syn and perform antigen presentation. (h) Recruiting of B and T cells and vesicle trafficking of pathological α-Syn give rise to infiltration of inflammatory factors and peripheral pathological α-Syn across the BBB. (i–l) Penetration of peripheral immune cells and peripheral pathological α-Syn causes central synucleinopathy and neuroinflammation. Created with Adobe Illustrator. BBB: Blood-brain barrier; CNS: central nervous system; FME: fibrillization microenvironment; RBC: red blood cell; α-Syn: α-synuclein.

Once pathological α-Syn is agglutinated in erythrocytes (possibly taking several decades before the observation of clinical manifestations caused by acute ischemic stroke, thoracic trauma, infection, etc.), it can activate and recruit peripheral immune cells, including B lymphocytes for antibody production and T lymphocytes for antigen presentation prior to neurodegeneration, in line with the clinical detection of α-Syn antibodies in the peripheral blood of PD patients (Xiao et al., 2014; Sulzer et al., 2017; Harms et al., 2018; Tulisiak et al., 2019; Wu et al., 2019; Karikari et al., 2022; Ruf et al., 2022; Li et al., 2023b). Although α-Syn antibodies help to eliminate pathological α-Syn in the peripheral blood and the activated autophagic and lysosomal proteins within these immune cells also promote an active process of proteasomal degradation of pathological α-Syn, the reaction of pathological α-Syn and its antibody still activates the complement system (Papagiannakis et al., 2015; Miki et al., 2018; Gregersen et al., 2021). Thorough activation of the peripheral immune and inflammatory system can directly promote the propagation of α-Syn pathology (Kim et al., 2022). Simultaneously, penetration of active T lymphocytes across the BBB into the brain has also been proven to cause neuroinflammation and aggravation of central α-Syn pathology, again proving the influence of the immune environment on α-Syn transmission (Williams et al., 2021). This in vivo regulation between the peripheral immune system and α-Syn pathology provides an explanation for the failure of antibody therapy in treating PD, owing to the counterforce of the immune system on promoting α-Syn pathology, indicating an immunity-centered FME contributing to the formation and propagation of peripheral α-Syn pathology (Lang et al., 2022; Pagano et al., 2022).

Conclusion

The production of pathological α-Syn in peripheral organs, the crosstalk between the body fluid and autonomic nervous system, the participation of BBB receptors, and the peripheral FME that affects α-Syn properties support peripheral organs as the source of PD pathology and even the initiation of α-Syn pathology. The existence of reverse diffusion from the blood to brain, from peripheral to central tissues, and the circulatory aggravation of α-Syn pathology on either side of the BBB urges us to understand the pathogenesis of PD from a systemic and global perspective. Therapies facilitating the clearance of peripheral α-Syn and inhibiting the forward and reverse transportation of peripheral and central α-Syn, early intervention of peripheral FME, and prevention of the circulatory spread of α-Syn pathology may alleviate the propagation of PD pathology. To date, the autonomic nerve pathway has been the most recognized route that mediates the transmission of pathological α-Syn from the periphery to the brain. Although emerging evidence has proven the existence of the body fluid pathway, there is a lack of feasibility in cutting off the body fluid connection as in the autonomic nerve pathway, bringing difficulties to further studies centering on humoral transmission of α-Syn pathology. In this review, we discussed the autonomic nerve pathway and body fluid circulation pathway as two separate mechanisms; however, we have not extended α-Syn pathology transmission to the crosstalk between the abovementioned two pathways. Whether pathological α-Syn in the bodily fluids can directly reach the brain parenchyma relying on body fluid circulation, or first interact with peripheral autonomic nerves and then indirectly reach the brain parenchyma needs further investigation.

Funding Statement

Funding: This work was supported by the National Natural Science Foundation of China, Nos. 82271447, 81771382; the National Key Research and Development Program of China, No. 2019YFE0115900; and the “New 20 Terms of Universities in Jinan”, No. 202228022 (all to ZZ).

Footnotes

Conflicts of interest: The authors declare no competing interest.

Data availability statement: The data are available from the corresponding author on reasonable request.

C-Editors: Li JY, Zhao M; S-Editors: Yu J, Li CH; L-Editors: Yu J, Song LP; T-Editor: Jia Y

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