Pathogenesis Of Α-synucleinopathies Research Articles

α-Synuclein pathology in Drosophila melanogaster is exacerbated by haploinsufficiency of Rop: connecting STXBP1 encephalopathy with α-synucleinopathies.

Syntaxin-binding protein 1 (STXBP1) is a presynaptic protein that plays important roles in synaptic vesicle docking and fusion. STXBP1 haploinsufficiency causes STXBP1 encephalopathy (STXBP1-E), which encompasses neurological disturbances including epilepsy, neurodevelopmental disorders, and movement disorders. Most patients with STXBP1-E present with regression and movement disorders in adulthood, highlighting the importance of a deeper understanding of the neurodegenerative aspects of STXBP1-E. An in vitro study proposed an interesting new role of STXBP1 as a molecular chaperone for α-Synuclein (αSyn), a key molecule in the pathogenesis of neurodegenerative disorders. However, no studies have shown αSyn pathology in model organisms or patients with STXBP1-E. In this study, we used Drosophila models to examine the effects of STXBP1 haploinsufficiency on αSyn-induced neurotoxicity in vivo. We demonstrated that haploinsufficiency of Ras opposite (Rop), the Drosophila ortholog of STXBP1, exacerbates compound eye degeneration, locomotor dysfunction, and dopaminergic neurodegeneration in αSyn-expressing flies. This phenotypic aggravation was associated with a significant increase in detergent-insoluble αSyn levels in the head. Furthermore, we tested whether trehalose, which has neuroprotective effects in various models of neurodegenerative disorders, mitigates αSyn-induced neurotoxicity exacerbated by Rop haploinsufficiency. In flies expressing αSyn and carrying a heterozygous Rop null variant, trehalose supplementation effectively alleviates neuronal phenotypes, accompanied by a decrease in detergent-insoluble αSyn in the head. In conclusion, this study revealed that Rop haploinsufficiency exacerbates αSyn-induced neurotoxicity by altering the αSyn aggregation propensity. This study not only contributes to understanding the mechanisms of neurodegeneration in STXBP1-E patients, but also provides new insights into the pathogenesis of α-synucleinopathies.

Evaluation of an Adoptive Cellular Therapy-Based Vaccine in a Transgenic Mouse Model of α-synucleinopathy.

Aggregated α-synuclein, a major constituent of Lewy bodies plays a crucial role in the pathogenesis of α-synucleinopathies (SPs) such as Parkinson's disease (PD). PD is affected by the innate and adaptive arms of the immune system, and recently both active and passive immunotherapies targeted against α-synuclein are being trialed as potential novel treatment strategies. Specifically, dendritic cell-based vaccines have shown to be an effective treatment for SPs in animal models. Here, we report on the development of adoptive cellular therapy (ACT) for SP and demonstrate that adoptive transfer of pre-activated T-cells generated from immunized mice can improve survival and behavior, reduce brain microstructural impairment via magnetic resonance imaging (MRI), and decrease α-synuclein pathology burden in a peripherally induced preclinical SP model (M83) when administered prior to disease onset. This study provides preclinical evidence for ACT as a potential immunotherapy for LBD, PD and other related SPs, and future work will provide necessary understanding of the mechanisms of its action.

Clinical application of prion-like seeding in α-synucleinopathies: Early and non-invasive diagnosis and therapeutic development.

The accumulation and deposition of misfolded α-synuclein (α-Syn) aggregates in the brain is the central event in the pathogenesis of α-synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and multiple-system atrophy. Currently, the diagnosis of these diseases mainly relies on the recognition of advanced clinical manifestations. Differential diagnosis among the various α-synucleinopathies subtypes remains challenging. Misfolded α-Syn can template its native counterpart into the same misfolded one within or between cells, behaving as a prion-like seeding. Protein-misfolding cyclic amplification and real-time quaking-induced conversion are ultrasensitive protein amplification assays initially used for the detection of prion diseases. Both assays showed high sensitivity and specificity in detection of α-synucleinopathies even in the pre-clinical stage recently. Herein, we collectively reviewed the prion-like properties of α-Syn and critically assessed the detection techniques of α-Syn-seeding activity. The progress of test tissues, which tend to be less invasive, is presented, particularly nasal swab, which is now widely known owing to the global fight against coronavirus disease 2019. We highlight the clinical application of α-Syn seeding in early and non-invasive diagnosis. Moreover, some promising therapeutic perspectives and clinical trials targeting α-Syn-seeding mechanisms are presented.

Plasma immune markers in an idiopathic REM sleep behavior disorder cohort

IntroductionIncreasing evidence shows a strong association between idiopathic REM sleep behavior disorder (iRBD) and α-synucleinopathies. Recent studies have indicated an inflammatory mechanism in the pathogenesis of α-synucleinopathies. Whether peripheral inflammatory cytokines are altered in iRBD and can be biomarkers for predicting phenoconversion remains unclear. MethodsWe collected baseline plasma samples from 77 consecutive iRBD patients and 64 age- and sex-matched healthy controls. Ten cytokines were measured: Interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-α. All iRBD patients underwent clinical assessment tests at baseline, and 75 were prospectively followed and received assessments for parkinsonism or dementia. Cox regression analyses were used to evaluate the predictive value of plasma cytokines in a follow-up period of 6.0 years. ResultsTNF-α and IL-10 were significantly elevated in iRBD compared with controls (both p < 0.001). IL-6/IL-10 and IL-8/IL-10 were significantly reduced in iRBD than in controls (p = 0.001, p < 0.001, respectively). After a median follow-up of 3.7 years, 16 iRBD patients developed neurodegenerative synucleinopathies. iRBD patients with higher TNF-α/IL-10 levels were more likely to develop neurodegenerative diseases (adjusted HR 1.07, 95% CI 1.01–1.14). The coexistence of elevated TNF-α/IL-10 and possible mild cognitive impairment predicted an early conversion of iRBD to neurodegenerative synucleinopathies (adjusted HR 4.17, 95% CI 1.47–11.81). ConclusionsOur study supported the early involvement of peripheral inflammation in prodromal α-synucleinopathy. Plasma cytokines may be predictive of disease conversion in iRBD, while large-scale longitudinal studies are warranted to validate the assumption.

Anti-aggregation Effects of Phenolic Compounds on α-synuclein.

The aggregation and deposition of α-synuclein (αS) are major pathologic features of Parkinson’s disease, dementia with Lewy bodies, and other α-synucleinopathies. The propagation of αS pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate αS aggregation and propagation. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies, we and other groups reported that phenolic compounds inhibit αS aggregation including oligomerization, thereby ameliorating αS oligomer-induced cellular and synaptic toxicities. Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. Our recent studies on the brain-penetrating polyphenolic acids 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-hydroxyphenylacetic acid (3-HPPA), which are derived from gut microbiota-based metabolism of dietary polyphenols, demonstrated an in vitro ability to inhibit αS oligomerization and mediate aggregated αS-induced neurotoxicity. Additionally, 3-HPPA, 3,4-diHBA, 3-HBA, and 4-hydroxybenzoic acid significantly attenuated intracellular αS seeding aggregation in a cell-based system. This review focuses on recent research developments regarding neuroprotective properties, especially anti-αS aggregation effects, of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α-synucleinopathies.

α-Synuclein as Diagnostic Biomarker

Although α-synuclein protein (αS) undergoes aggregation from a monomer to assemblies, such as oligomers, protofibrils, and mature fibrils, the early intermediate aggregates, that is, oligomers, are considered to be the most toxic species in the pathogenesis of α-synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While it has been reported that the αS concentration in cerebrospinal fluid (CSF) is decreased significantly in patients with PD and DLB, there have been reports of the αS oligomer concentration being elevated in the CSF of patients with PD. Moreover, it is supposed that the αS oligomer concentration is also elevated in the blood of patients with PD. Recently, it has been reported that lower cerebrospinal β-amyloid (Aβ)1-40, Aβ1-42, and αS levels are associated with cognitive decline in PD. Further combination studies of the CSF and blood may lead to the establishment of the candidate αS as a biomarker for α-synucleinopathies, including PD and DLB.

Molecular Role of Ca2+ and Hard Divalent Metal Cations on Accelerated Fibrillation and Interfibrillar Aggregation of \u03b1-Synuclein

α-Synuclein (αSyn) is an intrinsically disordered protein, the aggregation of which is highly related to the pathology of diverse α-synucleinopathies. Various hard divalent metal cations have been shown to affect αSyn aggregation. Especially, Ca2+ is suggested to be a crucial ion due to its physiological relevance to α-synucleinopathies. However, the molecular origin of αSyn aggregation mediated by the metal ions is not fully elucidated. In this study, we revealed that hard divalent metal ions had almost identical influences on αSyn aggregation. Based on these similarities, the molecular role of Ca2+ was investigated as a representative metal ion. Herein, we demonstrated that binding of multiple Ca2+ ions induces structural transition of αSyn monomers to extended conformations, which promotes rapid αSyn fibrillation. Additionally, we observed that Ca2+ induced further interfibrillar aggregation via electrostatic and hydrophobic interactions. Our results from multiple biophysical methods, including ion mobility-mass spectrometry (IM-MS), synchrotron small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), provide detailed information on the structural change of αSyn and the aggregation process mediated by Ca2+. Overall, our study would be valuable for understanding the influence of Ca2+ on the aggregation of αSyn during the pathogenesis of α-synucleinopathies.

FKBP12-immunopositive inclusions in patients with α-synucleinopathies

α-Synuclein (α-SYN), a presynaptic protein with the tendency to aggregate, is linked to α-synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). α-SYN is the main component of round intracytoplasmic inclusions called Lewy bodies (LBs), which are the hallmark of PD and DLB. In addition, accumulation of amyloid-β and neurofibrillary tangles as in the pathology of Alzheimer’s disease has been found in the DLB brain. Glial cytoplasmic inclusions are an MSA-specific type of inclusion found in oligodendrocytes and mainly comprise α-SYN. FK506-binding protein (FKBP) 12 is a member of the immunophilin family with peptidyl-prolyl isomerase activity that promotes protein folding and is believed to act as a chaperone protein. Previous in vitro work indicated that FKBP12 accelerated α-SYN aggregation more than other peptidyl-prolyl isomerases. The enzymatic activity of FKBP12 increases the formation of α-SYN fibrils at subnanomolar concentrations. In this study, we found that FKBP12 colocalized with α-SYN in LBs and neurites in PD and DLB brains. Furthermore, FKBP12-immunopositive neurofibrillary tangles colocalized with phosphorylated tau in DLB and FKBP12-immunopositive glial cytoplasmic inclusions colocalized with α-SYN in MSA. These findings suggest that FKBP12 is linked to the accumulation of α-SYN and phosphorylated tau protein in α-synucleinopathies. FKBP12 may play important roles in the pathogenesis of α-synucleinopathies through its strong aggregation function. Thus, FKBP12 could be an important drug target for α-synucleinopathies.

The Oligomer Hypothesis in α-Synucleinopathy.

Lewy bodies and Lewy neurites in the brain constitute the main histopathological features of Parkinson's disease (PD) and dementia with Lewy bodies. They comprise amyloid-like fibrils composed of α-synuclein (αS), a small protein (~14kDa). Because the aggregation of αS in the brain has been implicated as a critical step in the development of these diseases, the research for disease-modifying drugs has focused on modification of the αS aggregation process in the brain. Recent studies using synthetic αS peptides, a cell culture model, transgenic mice models, and human samples such as cerebrospinal fluids and the blood of PD patients have suggested that pre-fibrillar forms of αS (i.e., oligomers) are more critical than fibrillar forms (such as Lewy bodies) in the pathogenesis of α-synucleinopathies. Based on the accumulating evidence that oligomers play a central role in the pathogenesis of PD and other α-synucleinopathies (the "oligomer hypothesis"). This report reviews the recent findings regarding the oligomer hypothesis in the research of α-synucleinopathies.

MicroRNA-7 Enhances Subventricular Zone Neurogenesis by Inhibiting NLRP3/Caspase-1 Axis in Adult Neural Stem Cells.

α-Synuclein (α-syn) has been recognized to induce neuroinflammation and to disturb nerve repair process in Parkinson's disease. However, the potential mechanisms underlying α-syn-induced impairment of adult neurogenesis remain unclear. In the present study, A53T mutant α--synuclein transgenic (A53Ttg/tg) mice, caspase-1 knockout mice, and A53Ttg/tg;caspase-1-/- double transgenic mice were used to prepare adult neural stem cells (ANSCs) and to investigate inflammasome-related mechanism for α-syn-impaired neurogenesis in mouse subventricular zone (SVZ). We showed that α-syn inhibited neurogenesis in the SVZ of A53Ttg/tg mice and impaired proliferation and differentiation in ANSCs cultured in vitro, accompanied by reduced microRNA-7 (miR-7) expression levels. We further found that ANSC expressed NLRP3-containing inflammasome and α-syn activated both TLR4/NF-κB and NLRP3/caspase-1 signals in ANSCs. Either Nlrp3 knockdown or Caspase-1 knockout could attenuate the inhibition of proliferation in ANSCs induced by α-syn. Furthermore, we demonstrated that miR-7 post-transcriptionally controlled Nlrp3 expression besides targeting α-syn. Most notably, stereotactic injection of miR-7 mimics into lateral ventricles significantly inhibited NLRP3 inflammasome activation and improved adult neurogenesis in mouse SVZ. Our study provides a direct link between NLRP3 inflammasome activation and α-syn-impaired neurogenesis in the pathogenesis of α-synucleinopathies.

Phenolic compounds prevent the oligomerization of α-synuclein and reduce synaptic toxicity.

Lewy bodies, mainly composed of α-synuclein (αS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited αS fibrillation and destabilized preformed αS fibrils. Cumulative evidence suggests that low-order αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on αS oligomerization. Using methods such as photo-induced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited αS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of αS, whereas direct binding of RA to monomeric αS was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated αS synaptic toxicity by inhibition of αS oligomerization. These results suggest that Myr and RA prevent the αS aggregation process, reducing the neurotoxicity of αS oligomers. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds on α-synuclein (αS) oligomerization. Phenolic compounds, especially Myricetin (Myr) and Rosmarinic acid (RA), inhibited αS oligomerization and secondary structure conversion. Myr and RA ameliorated αS synaptic toxicity on the experiment of long-term potentiation. Our results suggest that Myr and RA prevent αS aggregation process and reduce the neurotoxicity of αS oligomers. Phenolic compounds are good candidates of disease modifying drugs for α-synucleinopathies.

Cerebral potential biomarkers discovery and metabolic pathways analysis of α-synucleinopathies and the dual effects of Acanthopanax senticosus Harms on central nervous system through metabolomics analysis

Ethnopharmacological relevanceAcanthopanax senticosus Harms (AS), also called “Ciwujia” in Chinese and “Siberian ginseng” in the Siberian Taiga region, is the herb used in traditional medicinal systems of China, Russia, Japan and Korea for the treatment of various nervous and cerebrovascular diseases. Aim of the study: Our pre-study has showed that AS can significantly suppress α-synuclein overexpression and toxicity. Neuronal protein α-synuclein is a key player in the development of neurodegenerative diseases called α-synucleinopathies. Identifying the potential biomarkers related to α-synucleinopathies may facilitate understanding the pathogenesis of the diseases and the safe application of AS in the clinic. Methods and resultsUltra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS) coupled with pattern recognition methods was integrated to examine the cerebral metabolic signature of human α-synuclein transgenic mice and the effects of AS on central nervous system (CNS) in pathology and physiology. Totally, 17 differentially expressed metabolites in wild type (WT) group and 26 in A30P mutant (A30P) group were identified and considered as potential biomarkers. Among them, 11 endogenous metabolites in WT+AS group and 18 in A30P+AS group were involved in the anti-α-synucleinopathies mechanism of AS. However, western blot and metabolomics analysis showed the effects of AS on CNS in physiology were opposite to those in pathology, which may cause potential neurotoxicity. ConclusionsThis study demonstrated that endogenous metabolites perturbation was involved in the pathogenesis of α-synucleinopathies and AS produced the dual effects on pathological and physiological CNS.

Disease-Modifying Effect of Adiponectin in Model of α-Synucleinopathies.

ObjectiveGrowing evidence suggests that neurodegenerative diseases are associated with metabolic disorders, but the mechanisms are still unclear. Better comprehension of this issue might provide a new strategy for treatment of neurodegenerative diseases. We investigated possible roles of adiponectin (APN), the antidiabetes protein, in the pathogenesis of α-synucleinopathies.MethodsUsing biochemical and histological methods, we investigated autopsy brain of α-synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and analyzed the effects of APN in cellular and in mouse models of α-synucleinopathies.ResultsWe observed that APN is localized in Lewy bodies derived from α-synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies. In neuronal cells expressing α-synuclein (αS), aggregation of αS was suppressed by treatment with recombinant APN in an AdipoRI-AMP kinase pathway-dependent manner. Concomitantly, phosphorylation and release of αS were significantly decreased by APN, suggesting that APN may be antineurodegenerative. In transgenic mice expressing αS, both histopathology and movement disorder were significantly improved by intranasal treatment with globular APN when the treatment was initiated in the early stage of the disease. In a mouse model, reduced levels of guanosine and inosine monophosphates, both of which are potential stimulators of aggregation of αS, might partly contribute to suppression of aggregation of αS by APN.InterpretationTaken together, APN may suppress neurodegeneration through modification of the metabolic pathway, and could possess a therapeutic potential against α-synucleinopathies.

Immunohistochemical localization of spatacsin in α-synucleinopathies

Spatacsin (SPG11) is a major mutated gene in autosomal recessive spastic paraplegia with thin corpus callosum (ARHSP-TCC) and is responsible for juvenile Parkinsonism. To elucidate the role of spatacsin in the pathogenesis of α-synucleinopathies, an immunohistochemical investigation was performed on the brain of patients with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) using anti-spatacsin antibody. In PD, Lewy bodies (LBs) in the brain stem were positive for spatacsin. These LBs showed intense staining in their peripheral portions and occasionally in the central cores. Lewy neurites were also spatacsin-positive. In DLB, cortical LBs were immunolabeled by spatacsin. In MSA, glial cytoplasmic inclusions (GCI) and a small fraction of neuronal cytoplasmic inclusions (NCI) were positive for spatacsin. The widespread accumulation of spatacsin observed in pathologic α-synuclein-containing inclusions suggests that spatacsin may be involved in the pathogenesis of α-synucleinopathies.

Diversity of Mitochondrial Pathology in a Mouse Model of Axonal Degeneration in Synucleinopathies

There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis of α-synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In particular, recent studies have demonstrated that failure of mitochondrial quality control caused by loss of function of the PTEN-induced kinase 1 (PINK1, PARK6) Parkin (PARK2) pathway may be causative in some familial PD. In sporadic PD, α-synuclein aggregation may interfere with mitochondrial function, and this might be further exacerbated by leucine-rich repeat kinase 2 (LRRK2). The majority of these findings have been obtained in Drosophila and cell cultures, whereas the objective of this paper is to discuss our recent results on the axonal pathology of brains derived from transgenic mice expressing α-synuclein or DLB-linked P123H β-synuclein. In line with the current view of the pathogenesis of sporadic PD, mitochondria abnormally accumulated in α-synuclein/LRRK2-immunopositive axonal swellings in mice expressing α-synuclein. Curiously, neither mitochondria nor LRRK2 was present in the swellings of mice expressing P123H β-synuclein, suggesting that α- and β-synuclein might play differential roles in the mitochondrial pathology of α-synucleinopathies.

Inhibition of α‐synuclein aggregation by small heat shock proteins

The fibrillization of α-synuclein (α-syn) is a key event in the pathogenesis of α-synucleinopathies. Mutant α-syn (A53T, A30P, or E46K), each linked to familial Parkinson's disease, has altered aggregation properties, fibril morphologies, and fibrillization kinetics. Besides α-syn, Lewy bodies also contain several associated proteins including small heat shock proteins (sHsps). Since α-syn accumulates intracellularly, molecular chaperones like sHsps may regulate α-syn folding and aggregation. Therefore, we investigated if the sHsps αB-crystallin, Hsp27, Hsp20, HspB8, and HspB2B3 bind to α-syn and affect α-syn aggregation. We demonstrate that all sHsps bind to the various α-syns, although the binding kinetics suggests a weak and transient interaction only. Despite this transient interaction, the various sHsps inhibited mature α-syn fibril formation as shown by a Thioflavin T assay and atomic force microscopy. Interestingly, HspB8 was the most potent sHsp in inhibiting mature fibril formation of both wild-type and mutant α-syn. In conclusion, sHsps may regulate α-syn aggregation and, therefore, optimization of the interaction between sHsps and α-syn may be an interesting target for therapeutic intervention in the pathogenesis of α-synucleinopathies.

Proteasome inhibition induces α-synuclein SUMOylation and aggregate formation

Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are characterized pathologically by intraneuronal inclusions called Lewy bodies (LBs) and Lewy neurites. A major component of these inclusions is the protein α-synuclein, which is natively unfolded but forms oligomers and insoluble fibrillar aggregates under pathological conditions. Although α-synuclein is known to undergo several posttranslational modifications, the contribution of SUMOylation to α-synuclein aggregation and the pathogenesis of α-synucleinopathies have not been elucidated. Here, we provide evidence that aggregates and inclusions formed as a result of impaired proteasome activity contain SUMOylated α-synuclein. Additionally, SUMO1 is present in the halo of LBs colocalizing with α-synuclein in the brains of PD and DLB patients. Interestingly, SUMOylation does not affect the ubiquitination of α-synuclein. These findings suggest that proteasomal dysfunction results in the accumulation of SUMOylated α-synuclein and subsequently its aggregation, pointing to the contribution of this posttranslational modification to the pathogenesis of inclusion formation in α-synucleinopathies.

Glial dysfunction in the pathogenesis of α-synucleinopathies: emerging concepts

Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are adult onset neurodegenerative disorders characterised by prominent intracellular α-synuclein aggregates (α-synucleinopathies). The glial contribution to neurodegeneration in α-synucleinopathies was largely underestimated until recently. However, brains of PD and DLB patients exhibit not only neuronal inclusions such as Lewy bodies or Lewy neurites but also glial α-synuclein aggregates. Accumulating experimental evidence in PD models suggests that astrogliosis and microgliosis act as important mediators of neurodegeneration playing a pivotal role in both disease initiation and progression. In MSA, oligodendrocytes are intriguingly affected by aberrant cytoplasmic accumulation of α-synuclein (glial cytoplasmic inclusions, Papp-Lantos bodies). Converging evidence from human postmortem studies and transgenic MSA models suggests that oligodendroglial dysfunction both triggers and exacerbates neuronal degeneration. This review summarises the wide range of responsibilities of astroglia, microglia and oligodendroglia in the healthy brain and the changes in glial function associated with ageing. We then provide a critical analysis of the role of glia in α-synucleinopathies including putative mechanisms promoting a chronically diseased glial microenvironment which can lead to detrimental neuronal changes, including cell loss. Finally, major therapeutic strategies targeting glial pathology in α-synucleinopathies as well as current pitfalls for disease-modification in clinical trials are discussed.

Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity

In Parkinson disease (PD), alpha-synuclein aggregates called Lewy bodies often involve and sequester Septin4 (Sept4), a polymerizing scaffold protein. However, the pathophysiological significance of this phenomenon is unclear. Here, we show the physiological association of Sept4 with alpha-synuclein, the dopamine transporter, and other presynaptic proteins in dopaminergic neurons; mice lacking Sept4 exhibit diminished dopaminergic neurotransmission due to scarcity of these presynaptic proteins. These data demonstrate an important role for septin scaffolds in the brain. In transgenic mice that express human alpha-synuclein(A53T) (a mutant protein responsible for familial PD), loss of Sept4 significantly enhances neuropathology and locomotor deterioration. In this PD model, insoluble deposits of Ser129-phosphorylated alpha-synuclein(A53T) are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects alpha-synuclein against self-aggregation and Ser129 phosphorylation. Taken together, these data show that Sept4 may be involved in PD as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance alpha-synuclein neurotoxicity.

Stabilization of alpha-synuclein protein with aging and familial parkinson's disease-linked A53T mutation.

We examined the potential relationship between aging and alpha-synuclein (alpha-Syn) metabolism, both of which are implicated in the pathogenesis of Parkinson's disease (PD) and other alpha-synucleinopathies. During aging,alpha-Syn and beta-Syn mRNA expression in brain decreases, but the protein levels are maintained at high levels. Significantly, the alpha-Syn protein level increases with aging in human substantia nigra. Pulse-chase analyses of alpha-Syn half-lives in neurons and neuronal cell lines indicate that, in mature neurons, the expression of alpha-Syn is regulated by the post-translational stabilization of alpha-Syn protein. Moreover, A53T mutant human alpha-Syn exhibits increased stability in neuronal cell lines, leading to higher levels of the mutant protein in cells and transgenic mice. Inhibitor studies suggest that the proteasomal and lysosomal systems may not be responsible for the differential stabilization or metabolism of alpha-Syn protein in neuronal cells. Because increased stabilization of alpha-Syn protein is associated with increased protein levels and accumulation of pathogenic protein modifications, such as oxidative damage, the stabilization of alpha-Syn with aging may be a significant factor in the pathogenesis of alpha-synucleinopathies.