Hot Topics in Recent Parkinson’s Disease Research: Where We are and Where We Should Go

Abstract

Parkinson’s disease (PD), the second most common neurodegenerative disease, is clinically characterized by both motor and non-motor symptoms. Although overall great achievements have been made in elucidating the etiology and pathogenesis of PD, the exact mechanisms of this complicated systemic disease are still far from being clearly understood. Consequently, most of the currently-used diagnostic tools and therapeutic options for PD are symptomatic. In this perspective review, we highlight the hot topics in recent PD research for both clinicians and researchers. Some of these hot topics, such as sleep disorders and gut symptoms, have been neglected but are currently emphasized due to their close association with PD. Following these research directions in future PD research may help understand the nature of the disease and facilitate the discovery of new strategies for the diagnosis and therapy of PD.

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease and is currently imposing a heavy economic and social burden on society as the population continues to age [1, 2]. PD is clinically characterized by motor dysfunctions (including resting tremor, bradykinesia, rigidity, and postural instability) and various non-motor symptoms (such as sleep, smell, gastrointestinal, cognitive, and neuropsychiatric disorders) [2–4]. Currently available pharmacological therapeutics for PD includes levodopa, dopamine (DA) agonists, and monoamine oxidase-B inhibitors to restore normal DA levels [5]. In addition, non-pharmacological options such as deep brain stimulation and repeated transcranial magnetic stimulation as alternative remedies have also been demonstrated to be effective for PD [5–7]. However, due to the limited understanding of the exact pathological and molecular basis of PD, these currently-available treatments are only symptomatic, rather than disease-modifying, and do not halt the ultimate progression of the disease. In addition, these therapies, both pharmacological and non-pharmacological, have side-effects that warrant the investigation of new interventions. For example, the gold standard of PD therapy, levodopa, is associated with significant adverse events including motor fluctuations and dyskinesias. Moreover, the clinical use of novel therapeutic strategies, such as cell therapy and gene therapy, at the current stage is still limited due to ethical and safety concerns [8]. The development of novel disease-modifying agents for PD treatment depends on a better understanding of the risk factors and pathological mechanisms of the disease, which should be the focus of future studies in PD. Worth noting, due to the long preclinical stage of PD and overlapping of PD symptoms with other diseases, the late diagnosis or misdiagnosis of this disease is common, which lead to delayed treatment and loss of the early therapeutic benefits. Therefore, disease-specific and early-stage biomarkers of PD should be emphasized and are urgently required. Here, in this perspective review, we highlight eight hot topics in recent PD research for clinicians and researchers to facilitate their efforts for understanding the nature of the disease and discovering novel strategies for PD diagnosis and therapy.

Topic 1: PD Pathogenesis from Gut to Brain

PD is pathologically characterized by intraneuronal α-synuclein (α-syn) aggregates and loss of DA neurons in the substantia nigra pars compacta (SNc). The Braak hypothesis proposes that α-syn pathology spreads from the gastrointestinal tract via the vagus nerve to the ventral midbrain and induces damage to DA neurons in the SNc. This hypothesis is based on postmortem observations of the pattern of Lewy body (LB) pathology in the human brain [9]. In most PD patients at early stages, LB pathology is often first detected in the olfactory bulb or in the intermediate reticular zone and dorsal motor nucleus of the vagus (DMV) in the medulla [10]. It then spreads to affect the midbrain, including the SNc and other regions during later stages of the disease.

Despite the discoveries of the inter-neuronal [11, 12] and inter-regional transport of α-syn, in an epidemiological study, complete (but not selective) truncal vagotomy has been associated with a decreased risk for subsequent PD, suggesting that the vagus nerve plays a crucial role in the pathogenesis of the disease [13]. Consistent with this, one recent study has further revealed that truncal vagotomy prevents the spread of pathological α-syn from the peripheral gut to the brain in animal models [14]. In this study, in order to mimic the spread of pathological α-syn in PD, Kim et al. developed a method in which α-syn fibrils are injected into the muscularis layer of the pylorus and duodenum. The pathological α-syn spreads sequentially from the DMV to caudal portions of the hindbrain, and later to the basolateral amygdala, dorsal raphe nucleus, and SNc, accompanied by both motor and non-motor symptoms. Much more interestingly, the spread of α-syn pathology from the periphery to the brain can be prevented by truncal vagotomy. However, no transmission has been reported in the α-syn knockout mouse [14]. These findings suggest that the vagus nerve plays critical roles in the α-syn pathology of PD, apparently ascending from the periphery to the brain. However, it is still not clear whether all DA neurons affected by α-syn will eventually form LB aggregates and the consequent DA neuronal loss. In fact, although striatal injection of α-syn leads to pathological spread in the SNc, LB pathology is rarely found in the striatum [15]. Further studies are needed to elucidate the exact cellular processes, molecular mechanisms, and pathological consequences of this vagus-mediated transport of α-syn pathology.

Despite the pathological toxicity of α-syn, the gut microbiota has also been connected with the onset and progression of PD. Intestinal infection with Gram-negative bacteria in young Pink1-knockout mice leads to a sharp decrease in the density of DAergic axonal varicosities in the striatum and triggers PD-like motor impairments later in life, which can be reversed by levodopa [16]. The higher content of bacterial tyrosine decarboxylases in the proximal small intestine, the site of levodopa absorption, has significant impact on the levodopa level in the plasma of rats [17]. However, it is still unknown whether these differences are correlated with other genetic risk factors or prodromal conditions of PD, for example, with SNCA (Synuclein Alpha) or idiopathic rapid eye movement sleep behavior disorder (RBD). Recently, the abundances of specific bacterial taxa have been reported to differ between PD patients and healthy controls, such as the enrichment of Anaerotruncus, Aquabacterium, Butyricicoccus, Clostridium IV and XVIII, Holdemania, and Sphingomonas in PD patients [18]. In another study, compared with healthy control subjects, approximately 80% of the differential gut microbes in PD showed trends similar to those in idiopathic RBD (Anaerotruncus spp. and Clostridium XIVb) and correlated with non-motor symptoms (Anaerotruncus and Akkermansia). These findings highlight the possibility that metagenomics can serve as promising tool to identify and characterize the microbial taxa that are enriched or depleted in PD with idiopathic RBD [19]. These alterations may also predict the possible therapeutic potential of the regulation of specific gut microbial taxa against PD. In fact, recent experimental evidence has indicated that the modulation or restoration of gut microbial taxa provides promising therapeutic benefits. Sun et al. have reported the neuroprotective effects of fecal microbiota transplantation on MPTP-induced PD mice [20]. Moreover, patients with inflammatory bowel disease have been reported to show a higher incidence of PD, which can be substantially reduced by early treatment with anti-inflammatory anti-tumor necrosis factor therapy [21]. All these findings support the concept of a systematic therapeutic strategy from a new point of view.

It is worth noting that so far, there is no animal model that accurately mimics PD, therefore it is critical to find out if the inter-neuronal spread of misfolded α-syn from gut to brain occurs in humans. Moreover, the frequency and density of aggregated α-syn are low in the peripheral autonomic nervous system, and especially in the enteric nervous system, raising the concern of monitoring endogenous α-syn. Finally, the formation of LB pathology is still undetectable in most studies of peripheral α-syn implantation. Therefore, to provide a definitive answer, there is still much work to be done [22].

Topic 2: Role of Neuroinflammation in PD

Neuroinflammation is a host-defense mechanism associated with the restoration of normal structure and function of the brain. However, over-activated neuroinflammation is one of the primary driving forces or mediators of neurodegeneration. Chronic neuroinflammation is recognized as one of the important hallmarks of PD pathology. Both post-mortem analyses of PD patients and experimental studies in animal models of PD have indicated that, as common features of PD, chronic glial activation and the consequent overproduction of pro-inflammatory factors exacerbates DA neuron loss in the SNc. A better understanding of the role of neuroinflammation in the PD brain will help to further understand the pathological mechanisms and discover effective therapeutic targets.

Microglia and astrocytes, the primary cells associated with neuroinflammation, are activated following insult or injury to the CNS, as shown by the changes in their morphology and phenotype. Upon activation, astrocytes and microglia can be categorized as either having the neurotoxic (A1/M1) or the neuroprotective (A2/M2) phenotype, depending on the mode of activation. In addition, crosstalk between neurons, astrocytes, and microglia plays a pivotal role in neuroinflammation [23]. For example, microglial activation induced by classical inflammatory mediators converts astrocytes into the neurotoxic A1 phenotype in a variety of neurological diseases [24]. In addition, glucagon-like peptide 1 receptor agonists directly prevent the microglia-mediated conversion of astrocytes to the A1 phenotype [25], and therefore protect against the loss of DA neurons and the behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD, as well as reducing the behavioral deficits and neuropathological abnormalities in the human A53T α-syn transgenic mouse model [25]. The development of agents that inhibit the formation of A1 astrocytes could provide a promising strategy to treat these diseases. Worth noting, recent evidence has suggested that both astrocytes and microglia display a wide range of phenotypes depending on the activating stimuli [26, 27]. Apart from microglia and astrocytes, Galiano-Landeira et al. recently found an increase in the level of CD8 T cells in PD patients, which is positively correlated with neuronal death in the SNc. Moreover, robust CD8 T cell infiltration precedes α-syn aggregation and DAergic neuronal death in the earliest stage of the disease and is paralleled by α-syn accumulation and neuronal death throughout stages II to IV. These results showed that nigral infiltration by cytotoxic CD8 T cells is an earlier pathogenic event than pathological α-syn aggregation and neuronal death, and may initiate and propagate neuronal death and synucleinopathy in PD [28].

Current research has indicated an important role of neuroinflammation in PD, therefore it is definitely a promising way to design or test therapeutics to prevent or halt the neuronal damage caused by neuroinflammation. Based on this idea, it becomes an urgent task to explore the molecular mechanisms for maintaining the homeostasis of neuroinflammation and identifying the key molecules to promote the pro-resolving or self-healing ability of DA neurons [29]. Indeed, the rat PD model overexpressing human α-syn displays alterations in nigral DA degeneration and motor deficits, as well as neuroinflammation, which can be reversed by the inflammation-suppressor resolvin D1, indicating that targeting resolvins may ameliorate inflammation and PD [30]. Moreover, several transcription factors, such as Nrf2, Nurr1, and TCF4, also play important roles in neuroinflammation and DA neuronal loss in PD. Functional modulation of these molecules may delay or halt the disease progression [31–33]. Future studies should focus on the therapeutics that target cellular crosstalk and the induction and/or resolution of inflammation. Novel techniques to measure inflammatory biomarkers to detect or monitor active CNS inflammation should be developed to guarantee the successful translation of immunotherapeutic agents from the preclinical stage.

Experimental studies in animal models have indicated the activation of neuroinflammation in PD and support the application of immunomodulatory agents for PD therapy. Unfortunately, there have been several challenges in confirming the efficacy of these potential therapeutic candidates. First of all, the differences in the immune systems between rodents and humans may be a barrier for the successful translation of preclinical candidates into real clinical practice. Secondly, rodents do not naturally develop α-synucleinopathies, therefore the induction and progression of PD in rodents via overexpression or injection of human α-syn (oligomer or fibrils) are over-artificial. Future studies establishing nonhuman primate models or humanized mouse models bearing human leukocyte antigen may help overcome these problems.

Topic 3: Sleep Disorders in PD

Increasing lines of evidence have demonstrated the impact of sleep and sleep disorders on the brain. Sleep disorders, especially RBD and sleep-disordered breathing, the most frequent non-motor manifestations of PD, substantially impair the quality of life of PD patients. Moreover, sleep disorders have recently been demonstrated to be involved in the course of the disease. However, the structural basis and molecular mechanisms underlying the correlations between sleep disorders and PD pathologies such as α-synucleinopathies are still not well established.

Recently, Shen et al. recapitulated RBD-like behaviors in a PD mouse model with α-syn fibril injection in the sublaterodorsal tegmental nucleus (STN). They further identified α-synucleinopathy and DA neuron loss within the STN [34]. Moreover, these α-synucleinopathy-based RBD mice display parkinsonian locomotor dysfunction and PD-like non-motor symptoms, such as depressive disorder, olfactory dysfunction, and gastrointestinal dysmotility. Furthermore, the seeded α-syn in the STN can spread not only to the SNC, olfactory bulb and DMV, but also within the peripheral submucosal and myenteric plexuses, which may contribute to the motor and non-motor parkinsonian-like manifestations. While this study demonstrates a causal role of pathological α-syn in sleep disorders, the impact of other PD-causal or risk genes, such as LRRK2, GBA. and DJ1, on sleep/wake cycles should be further determined [35]. Moreover, sleep deprivation or restriction studies in animals should be performed as a priority in future research to explore the dynamic properties and molecular mechanisms of sleep disorders in the occurrence and progression of PD pathologies

In addition to RBD, obstructive sleep apnea (OSA) is also considered to be a common comorbidity of PD. One recent meta-analysis has revealed that OSA is closely associated with the severity of PD-associated cognitive dysfunction and motor symptoms [36]. The exact mechanisms by which OSA influences the motor and cognitive functions in PD, and the possible impact of OSA on the neurodegenerative process of PD should be further investigated.

In addition, at the current stage, there still a lack of high-quality studies to determine the association and underlying mechanisms of sleep disorders, such as RBD, restless legs syndrome, and OSA in PD patients. Furthermore, there is not enough progress in the management of sleep disorders in PD patients. Considering the close relationship between circadian rhythm disturbance and PD, more attention and investigations are needed.

Topic 4: New Genetic and Epigenetic Discoveries in PD

The understanding of the genetic basis of PD has developed greatly over the past decades, since the discovery of SNCA gene mutation, which results in familial autosomal dominant PD. To date, at least 20 disease-causing genes for Parkinsonism, as well as genetic risk loci and sporadic PD phenotype genetic variants, have been identified [37, 38]. Although great achievements have been made in our understanding of the genetic basis of PD, further disease-causal or disease-risk genetic variability remains to be identified. The exact biological functions and pathogenic contributions of these genes to this complex disorder are still far from being clearly investigated. This will benefit from the aid of genome-wide technology to better understand the pathogenesis of familial and sporadic PD [39, 40]. Future studies should focus on the functions and mechanisms through which these variants of disease-causing genes impact disease occurrence and progression. For example, a recent study revealed that the minor allele at rs34311866, a common variant of TMEM175, is associated with an increased risk of developing PD and reduced lysosome K⁺ channel currents, which predisposes neurons to stress-induced damage and accelerates the accumulation of pathological α-syn [41].

To date, genome-wide association studies (GWASs) have identified at least 90 independent risk-associated variants [42, 43]. However, most of them were identified in patients of European ancestry and have rarely been investigated in other populations [43]. Future studies should be performed across diverse populations to identify potential novel loci for PD. Moreover, the application of novel techniques, such as single-cell RNA sequencing, genome sequencing, high-throughput screening, artificial intelligence, and machine learning, might greatly improve our understanding of the biological functions of genetic risk factors for PD.

In addition to genetic mutations, growing evidence has suggested that epigenetic mechanisms also contribute to the pathogenesis. For instance, studies have revealed regulated SNCA gene expression resulting from epigenetic modifications [44]. α-Syn itself has epigenetic properties, such as histone tail modification and DNMT1 sequestration. In addition, microRNAs are also able to modulate α-syn expression. Other PD-related genes have been found to be regulated by microRNA-related mechanisms. For example, decreased expression levels of DJ1, PINK1, and parkin proteins result from microRNA-mediated mechanisms in the PD brain [45–48]. Increasing studies aiming to explore the epigenetic basis of PD have helped better understand the molecular mechanisms involved in DAergic neuron loss, and have paved the way for a new epigenetic-modifying strategy to combat PD.

Future studies in PD should aim to identify novel genetic loci through GWASs and generate more biological insights to understand and further explore the correlations between (epi)genetic-based and lifestyle/environmental factors to better characterize individuals at risk and develop novel therapeutic approaches [49].

Topic 5: Autophagy and Mitophagy Impairment in PD

PD is pathologically characterized by progressive DA neuron loss accompanied by LB aggregates with abnormal α-syn fibrillation as a major protein component [50]. Other pathological events, including amyloid-β deposition and neurofibrillary tangles, are also detectable markers in different regions of the PD brain [51]. Malfunction of protein degradation pathways, such as autophagy, has been found to be involved in these abnormal protein aggregations and the pathogenesis of PD. In eukaryotic cells, autophagy is a self-degradative process important for the removal of long-lived proteins and dysfunctional intracellular organelles. Increasing lines of evidence have suggested that aggregation of α-syn or tau is a consequence of impaired autophagic lysosomal degradation [51, 52]. In turn, α-syn and tau also impact mitochondrial, autophagic, and lysosomal functions. Considering the high metabolic activity and mitochondrial energy demand of DA neurons, these cells are definitely and especially vulnerable to the insufficient clearance of damaged mitochondria, which leads to increased reactive oxygen species to further accelerate disease progression. Recently, Grassi et al. found that conformationally distinct, non-fibrillar, phosphorylated α-syn species (pα-syn*) can induce mitochondrial toxicity and mitophagy, indicating that neurotoxic pα-syn* might be a key therapeutic target [53].

Increasing evidence has indicated a bidirectional pathogenic loop between the aggravated PD pathology and impaired autophagy, and an increased autophagic flux might compensate for the inhibited protein degradation. However, autophagy can act in either a pro-survival or a pro-death role and over-activated autophagy could be neurotoxic. To further explore the dynamic machinery and mechanisms of autophagy, it is crucial to identify the autophagic flux by a thorough analysis and to correlate the dynamic changes in different autophagy processes and pathways with the disease progression stages. Moreover, future findings of autophagy-regulating agents should be more specific to the proper degradative flux at different phases of the disease.

In addition, clinical translation of selective mitophagy modulators as therapeutic candidates is still urgently needed, due to the lack of such modulators. Although several compounds have been found to trigger mitophagy, these agents are not suitable for clinical application because of their toxicity and non-specificity. Yi et al. recently reported that several pathogenic Parkin variants can impair mitophagy [54], thus targeting these variants in the design of genotype-specific drugs may represent a promising direction.

Topic 6: Ferroptosis and Pyroptosis in PD

Ferroptosis is a recently-recognized non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation [55, 56]. Several pathological hallmarks of PD, including increased iron and decreased glutathione peroxidase 4 levels in the SN, elevated lipid peroxidation, and DJ-1 depletion, are known key features and/or triggers in the ferroptotic cell death pathway and strongly implicate the ferroptosis pathway in PD [57]. Ferroptosis may help explain the vicious interactions between α-synucleinopathy and iron accumulation, oxidative stress, and DA neuron loss in PD. However, while iron chelators with anti-ferroptotic activity have shown promising clinical benefits in independent clinical trials on early PD, their clinical application is still limited due to their poor ability to cross the blood brain barrier (BBB). Various developing strategies have been established to overcome this limitation, including modifying anti-ferroptotic molecules with BBB-permeable peptides or packaging anti-ferroptotic agents within nanomaterials. Future studies should pay more attention to determining the therapeutic benefits of these novel materials in clinical trials and further confirm the important roles of ferroptosis in PD [58].

Other than ferroptosis, the dysregulation of pyroptosis promoted by toxic signals, including microbial infection or abnormal protein aggregation, is often associated with immune dysregulation and an excessive inflammatory response can result in a number of CNS diseases. More recently, several lines of evidence have indicated an important role of inflammasome/pyroptosis activation in PD. For example, activation of the NLRP3 (nucleotide-binding oligomerization domain-, leucine-rich repeat and pyrin domain-containing 3) inflammasome promotes massive secretion of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and induces pyroptosis to activate microglia to further release IL-1β. Abnormal α-syn aggregation activates NLRP3 inflammasomes, and PD-causing Parkin has also been closely associated with NLRP3. Moreover, a derivative of the immunosuppressant cyclosporine A, N-methyl-4-isoleucine-cyclosporine, is capable of suppressing rotenone-induced pyroptosis and down-regulating the expression levels of NLRP3, caspase-1 gasdermin-D, IL-1β, and IL-18 [59].

While most pyroptosis-related research on PD has focused on the role of the NLRP3 inflammasome, future studies should investigate and characterize other less well-known inflammasomes and their potentially important roles in PD. In addition, although the importance of inflammasome activation has been demonstrated in PD models, their specific roles in different CNS cell types (microglia, astrocytes, and neurons) have still rarely been investigated using cell-specific knockout mouse models. Moreover, novel techniques such as single-cell RNA sequencing and mass cytometry should be used to help to get a better view on the spectra of inflammasomes that are expressed in the different cell types. Finally, since pyroptosis has been identified as a critical mechanism driving inflammation-related DAergic dysregulation and PD pathologies, inhibiting inflammasomes and inflammasome signaling might be a potential anti-inflammatory approach for PD therapy.

Topic 7: Early Diagnosis and Biomarkers for PD

For better PD management, reliable diagnostic and prognostic biomarkers are urgently needed [60, 61]. To date, the diagnosis of PD relies mostly on the clinical symptoms, and this may delay its early detection and treatment at preclinical or prodromal stages. Various potential diagnostic and prognostic biomarkers have been established from biofluids, such as α-syn species, neurofilament light chain, and Nurr1, which closely reflect the pathophysiology of PD. A combination of multiple biomarkers may emerge as an accurate diagnostic and prognostic model [61].

With respect to the early diagnosis of PD, the measurement of CSF α-syn aggregates has provided encouraging preliminary results [62]. Detection of blood α-syn species, neurofilament light chain, and the transcription factor Nurr1 are also under investigation as potential early and differential diagnosis biomarkers for PD. In view of the application of CSF and blood biomarkers with improved PD diagnostic and prognostic accuracy, further clinical trials and tests should be performed in large independent cohort studies [63].

Notably, metabolic changes have been recognized as the most direct response to physiological and pathological conditions. By profiling biofluids, feces, and brain tissue, metabolomics analysis has become a powerful and promising tool to identify novel biomarkers and provide valuable insights into the early pathogenesis of PD. Metabolomics studies in both PD patients and experimental PD models have found that the combination of metabolomics analysis with other techniques, such as metagenomics, proteomics, transcriptomics, and the deep learning approach, may lead to a better understanding of PD etiology, the identification of potential novel biomarkers for PD diagnosis, and the discovery of therapeutic targets for effective treatment [64–66].

Topic 8: Novel Therapeutic Strategies for the Treatment of PD

Although the pathological characteristics of PD have been well described as the loss of DA neurons in the SN, the exact mechanisms underlying PD pathogenesis are still far from being clearly understood. Many genetic and environmental factors as well as their complicated interactions have been demonstrated to affect both the central and peripheral nervous systems, resulting in a broad spectrum of motor and non-motor manifestations of PD, including postural instability and falls, speech and swallowing dysfunction, autonomic failure, psychosis, sleep disorders, and dementia. Currently, most of the clinically-applied treatments are symptomatic. The most fundamental unmet need is disease-modifying therapy that can effectively change the course of the disease by slowing, halting, and, ideally, reversing the progression of PD pathologies. Unfortunately, no disease-modification attempts have succeeded to date. The exploration of novel therapeutic strategies based on new molecular mechanisms and targets is urgently needed [67].

Worth noting, current research on PD has revealed multifactorial pathological mechanisms of this disease. Consequently, multifunctionality has been demonstrated to be a key feature for the exploration of future therapeutic strategies against PD [68]. In fact, various multifunctional therapies targeting metal chelation, monoamine oxidase inhibition, and DA receptor interaction have been established and investigated for their efficiency in manipulating the multiple pathogenic process of PD. Moreover, experiments should also be performed to evaluate the potential impact of α-syn-aggregation inhibitors on metal or metal-induced α-syn aggregation. Notably, Nurr1, an important transcription factor with distinctive physiological features, has been identified as a crucial regulator of DA neuronal differentiation, survival, and a risk factor for PD. Furthermore, Nurr1 can inhibit the expression of pro-inflammatory mediators in microglia and astrocytes. Collectively, Nurr1 may serve as a promising target for neuroprotection via multifunctional mechanisms [69, 70].

Apart from chemical molecules, exosomes may also provide promising tools for future multifunctional therapy of PD [71]. Exosomes are specifically secreted vesicles containing various signaling messengers or functional molecules, including mRNAs, miRNAs, and proteins. Exosomes are important for intercellular communication, and are believed to be involved in various biological processes. Exosomes have also been considered as drug-carriers for the CNS due to their ability to cross the BBB. Considering the recent discoveries and developments of various engineered mammalian cell-based theranostic agents, mammalian cell implants in patients could secrete therapeutic exosomes loaded with biopharmaceutical-encoding mRNAs in situ, and would also have therapeutic potential [72].

Although much progress has been made in understanding the pathological roles of α-syn in PD, only limited achievements have been able to translate these discoveries into clinical usage. Further research and the development of novel antibodies and nano-biomaterials may provide opportunities for safe and effective therapeutic candidates against PD. For examples, PRX002/RG7935, a humanized monoclonal antibody targeting α-syn aggregates, is thought to halt the inter-neuronal spread of pathogenic α-syn, resulting in neuronal protection and delayed disease progression. The preclinical efficacy of the murine homologue of PRX002 (9E4) has been documented using both in vivo and in vitro experiments [72]. One recent randomized clinical trial (https://clinicaltrials.gov/ct2/show/NCT03100149) further revealed the general safety and good tolerance of PRX002. Graphene quantum dots (GQDs) have been reported to inhibit the fibrillization of α-syn and promote the disaggregation of mature α-syn fibrils. Moreover, in C57BL/6 mice with stereotaxic intra-striatal injection of α-syn PFF, GQDs can rescue neuronal death and synaptic loss, reduce LB formation, ameliorate mitochondrial dysfunctions, and prevent the interneuronal transmission of α-syn pathology [73].

Conclusion

PD is a complex, multifactorial, heterogeneous, and severe neurodegenerative disease. Many genetic and non-genetic factors responsible for PD have been identified. Impaired DA metabolism, neuroinflammation, and oxidative stress induced by abnormal protein aggregation and neurotoxins have been reported to be involved in PD pathogenesis and progression. Current treatment of PD involves pharmacological and non-pharmacologic approaches to ameliorate either motor or non-motor symptoms. Although overall great achievements have been made in understanding the pathogenesis of PD and improving the diagnosis and therapy for this disease, its management still faces many challenges. Future basic studies should focus on the interactions of genetic and environmental factors, the peripheral–to–central spread of PD pathology, and the exact molecular mechanisms of neuroinflammation and DA neuron death. Future work should also focus on the possible roles of non-motor symptoms, especially sleep disorders, in PD pathogenesis and progression. Novel techniques and animal models should be developed in order to discover reliable early biomarkers and effective disease-modifying agents for PD diagnosis and therapy. Furthermore, proper animal models that mimic non-motor symptoms, neuroinflammation, and the gut–brain spread of PD pathology, should be established to better understand the exact disease process and detailed molecular and pathological mechanism. Finally, novel techniques and methods such as various Omics analyses, nano technologies, and stem-cell-based strategies may provide new tools to develop multi-functional and disease-modifying agents to overcome the current limitations in PD research and clinical practice. For clinicians, further clarifying the potential correlations between non-motor symptoms with disease pathogenesis and progression during clinical practice is important. The successful establishment of banks of brains, biofluids, images, and genes from PD patients, together with clinical symptomatic descriptions and medication records, may also provide valuable big-data for discovering novel biomarkers and therapeutic targets. The explorations and successful achievements yielded by the above basic and clinical research directions may not only provide relief to patients with advanced PD, but also favorably modify its occurrence and progression at very early stages, and may eventually improve the quality of life of patients with PD (Fig. 1).

Fig. 1.

Hot topics in recent Parkinson’s disease research.