The usual suspects,dopamine and alpha‐synuclein,conspire to cause neurodegeneration

Parkinson's disease (PD) is primarily a movement disorder driven by the loss of dopamine‐producing neurons in the substantia nigra (SN). Early identification of the oxidative properties of dopamine implicated it as a potential source of oxidative stress in PD, yet few studies have investigated dopamine neurotoxicity in vivo. The discovery of PD‐causing mutations in α‐synuclein and the presence of aggregated α‐synuclein in the hallmark Lewy body pathology of PD revealed another important player. Despite extensive efforts, the precise role of α‐synuclein aggregation in neurodegeneration remains unclear. We recently manipulated both dopamine levels and α‐synuclein expression in aged mice and found that only the combination of these 2 factors caused progressive neurodegeneration of the SN and an associated motor deficit. Dopamine modified α‐synuclein aggregation in the SN, resulting in greater abundance of α‐synuclein oligomers and unique dopamine‐induced oligomeric conformations. Furthermore, disruption of the dopamine‐α‐synuclein interaction rescued dopaminergic neurons from degeneration in transgenic Caenorhabditis elegans models. In this Perspective, we discuss these findings in the context of known α‐synuclein and dopamine biology, review the evidence for α‐synuclein oligomer toxicity and potential mechanisms, and discuss therapeutic implications. © 2019 International Parkinson and Movement Disorder Society     

Stimulation of synaptoneurosome glutamate release by monomeric and fibrillated α‐synuclein

The α‐synuclein protein exists in vivo in a variety of covalently modified and aggregated forms associated with Parkinson's disease (PD) pathology. However, the specific proteoform structures involved with neuropathological disease mechanisms are not clearly defined. Since α‐synuclein plays a role in presynaptic neurotransmitter release, an in vitro enzyme‐based assay was developed to measure glutamate release from mouse forebrain synaptoneurosomes (SNs) enriched in synaptic endings. Glutamate measurements utilizing SNs from various mouse genotypes (WT, over‐expressers, knock‐outs) suggested a concentration dependence of α‐synuclein on calcium/depolarization‐dependent presynaptic glutamate release from forebrain terminals. In vitro reconstitution experiments with recombinant human α‐synuclein proteoforms including monomers and aggregated forms (fibrils, oligomers) produced further evidence of this functional impact. Notably, brief exogenous applications of fibrillated forms of α‐synuclein enhanced SN glutamate release but monomeric forms did not, suggesting preferential membrane penetration and toxicity by the aggregated forms. However, when applied to brain tissue sections just prior to homogenization, both monomeric and fibrillated forms stimulated glutamate release. Immuno‐gold and transmission electron microscopy (TEM) detected exogenous fibrillated α‐synuclein associated with numerous SN membranous structures including synaptic terminals. Western blots and immuno‐gold TEM were consistent with SN internalization of α‐synuclein. Additional studies revealed no evidence of gross disruption of SN membrane integrity or glutamate transporter function by exogenous α‐synuclein. Overall excitotoxicity, due to enhanced glutamate release in the face of either overexpressed monomeric α‐synuclein or extrasynaptic exposure to fibrillated α‐synuclein, should be considered as a potential neuropathological pathway during the progression of PD and other synucleinopathies. © 2017 Wiley Periodicals, Inc.     

Overexpression of α‐synuclein in an astrocyte cell line promotes autophagy inhibition and apoptosis

α‐Synuclein is the major component of neuronal cytoplasmic aggregates called Lewy bodies, the main pathological hallmark of Parkinson disease. Although neurons are the predominant cells expressing α‐synuclein in the brain, recent studies have demonstrated that primary astrocytes in culture also express α‐synuclein and regulate α‐synuclein trafficking. Astrocytes have a neuroprotective role in several detrimental brain conditions; we therefore analyzed the effects of the overexpression of wild‐type α‐synuclein and its A30P and A53T mutants on autophagy and apoptosis. We observed that in immortalized astrocyte cell lines, overexpression of α‐synuclein proteins promotes the decrease of LC3‐II and the increase of p62 protein levels, suggesting the inhibition of autophagy. When these cells were treated with rotenone, there was a loss of mitochondrial membrane potential, especially in cells expressing mutant α‐synuclein. The level of this decrease was related to the toxicity of the mutants because they show a more intense and sustained effect. The decrease in autophagy and the mitochondrial changes in conjunction with parkin expression levels may sensitize astrocytes to apoptosis.     

A new role for α‐synuclein in Parkinson's disease: Alteration of ER–mitochondrial communication

Familial cases of Parkinson's disease (PD) can be associated with overexpression or mutation of α‐synuclein, a synaptic protein reported to be localized mainly in the cytosol and mitochondria. We recently showed that wild‐type α‐synuclein is not present in mitochondria, as previously thought, but rather is located in mitochondrial‐associated endoplasmic reticulum membranes. Remarkably, we also found that PD‐related mutated α‐synuclein results in its reduced association with mitochondria‐associated membranes, coincident with a lower degree of apposition of endoplasmic reticulum with mitochondria and an increase in mitochondrial fragmentation, as compared with wild‐type. This new subcellular localization of α‐synuclein raises fundamental questions regarding the relationship of α‐synuclein to mitochondria‐associated membranes function, in both normal and pathological states. In this article, we attempt to relate aspects of PD pathogenesis to what is known about mitochondria‐associated membranes' behavior and function. We hypothesize that early events occurring in dopaminergic neurons at the level of the mitochondria‐associated membranes could cause long‐term disturbances that lead to PD. © 2015 International Parkinson and Movement Disorder Society     

Alpha‐synuclein in colonic submucosa in early untreated Parkinson's disease

The diagnosis of Parkinson's disease rests on motor signs of advanced central dopamine deficiency. There is an urgent need for disease biomarkers. Clinicopathological evidence suggests that α‐synuclein aggregation, the pathological signature of Parkinson's disease, can be detected in gastrointestinal tract neurons in Parkinson's disease. We studied whether we could demonstrate α‐synuclein pathology in specimens from unprepped flexible sigmoidoscopy of the distal sigmoid colon in early subjects with Parkinson's disease. We also looked for 3‐nitrotyrosine, a marker of oxidative stress. Ten subjects with early Parkinson's disease not treated with dopaminergic agents (7 men; median age, 58.5 years; median disease duration, 1.5 years) underwent unprepped flexible sigmoidoscopy with biopsy of the distal sigmoid colon. Immunohistochemistry studies for α‐synuclein and 3‐nitrotyrosine were performed on biopsy specimens and control specimens from a tissue repository (23 healthy subjects and 23 subjects with inflammatory bowel disease). Nine of 10 Parkinson's disease samples were adequate for study. All showed staining for α‐synuclein in nerve fibers in colonic submucosa. No control sample showed this pattern. A few showed light α‐synuclein staining in round cells. 3‐Nitrotyrosine staining was seen in 87% of Parkinson's disease cases but was not specific for Parkinson's disease. This study suggests a pattern of α‐synuclein staining in Parkinson's disease that was distinct from healthy subjects and those with inflammatory bowel disease. The absence of this pattern in subjects with inflammatory bowel disease suggests it is not a sequel of inflammation or oxidative stress. 3‐Nitrotyrosine immunostaining was common in all groups studied, suggesting oxidative stress in the colonic submucosa. © 2011 Movement Disorder Society.     

5‐S‐cysteinyldopamine neurotoxicity: Influence on the expression of α‐synuclein and ERp57 in cellular and animal models of Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose etiology is still unclear in spite of extensive investigations. It has been hypothesized that 5‐S‐cysteinyldopamine (CysDA), a catechol‐thioether metabolite of dopamine (DA), could be an endogenous parkinsonian neurotoxin. To gain further insight into its role in the neurodegenerative process, both CD1 mice and SH‐SY5Y neuroblastoma cells were treated with CysDA, and the data were compared with those obtained by the use of 6‐hydroxydopamine, a well‐known parkinsonian mimetic. Intrastriatal injection of CysDA in CD1 mice caused a long‐lasting depletion of DA, providing evidence of in vivo neurotoxicity of CysDA. Both in mice and in SH‐SY5Y cells, CysDA treatment induced extensive oxidative stress, as evidenced by protein carbonylation and glutathione depletion, and affected the expression of two proteins, α‐synuclein (α‐Syn) and ERp57, whose levels are modulated by oxidative insult. Real‐time PCR experiments support these findings, indicating an upregulation of both ERp57 and α‐Syn expression. α‐Syn aggregation was also found to be modulated by CysDA treatment. The present work provides a solid background sustaining the hypothesis that CysDA is involved in parkinsonian neurodegeneration by inducing extensive oxidative stress and protein aggregation. © 2013 Wiley Periodicals, Inc.     

Alpha‐synuclein in the appendiceal mucosa of neurologically intact subjects

Parkinson's disease is characterized by the pathological aggregation of Alpha‐synuclein. The dual‐hit hypothesis proposed by Braak implicates the enteric nervous system as an initial site of α‐synuclein aggregation with subsequent spread to the central nervous system. Regional variations in the spatial pattern or levels of α‐synuclein along the enteric nervous system could have implications for identifying sites of onset of this pathogenic cascade. We performed immunohistochemical staining for α‐synuclein on gastrointestinal tissue from patients with no history of neurological disease using the established LB509 antibody and a new clone, MJFR1, characterized for immunohistochemistry here. We demonstrate that the vermiform appendix is particularly enriched in α‐synuclein–containing axonal varicosities, concentrated in its mucosal plexus rather than the classical submucosal and myenteric plexuses. Unexpectedly, intralysosomal accumulations of α‐synuclein were detected within mucosal macrophages of the appendix. The abundance and accumulation of α‐synuclein in the vermiform appendix implicate it as a candidate anatomical locus for the initiation of enteric α‐synuclein aggregation and permits the generation of testable hypotheses for Parkinson's disease pathogenesis. © 2013 International Parkinson and Movement Disorder Society     

α‐Synuclein activates innate immunity but suppresses interferon‐γ expression in murine astrocytes

Glial activation and neuroinflammation contribute to pathogenesis of neurodegenerative diseases, linked to neuron loss and dysfunction. α‐Synuclein (α‐syn), as a metabolite of neuron, can induce microglia activation to trigger innate immune response. However, whether α‐syn, as well as its mutants (A53T, A30P, and E46K), induces astrocyte activation and inflammatory response is not fully elucidated. In this study, we used A53T mutant and wild‐type α‐syns to stimulate primary astrocytes in dose‐ and time‐dependent manners (0.5, 2, 8, and 20 μg/ml for 24 hr or 3, 12, 24, and 48 hr at 2 μg/ml), and evaluated activation of several canonical inflammatory pathway components. The results showed that A53T mutant or wild‐type α‐syn significantly upregulated mRNA expression of toll‐like receptor (TLR)2, TLR3, nuclear factor‐κB and interleukin (IL)‐1β, displaying a pattern of positive dose–effect correlation or negative time–effect correlation. Such upregulation was confirmed at protein levels of TLR2 (at 20 μg/ml), TLR3 (at most doses), and IL‐1β (at 3 hr) by western blotting. Blockage of TLR2 other than TLR4 inhibited TLR3 and IL‐1β mRNA expressions. By contrast, interferon (IFN)‐γ was significantly downregulated at mRNA, protein, and protein release levels, especially at high concentrations of α‐syns or early time‐points. These findings indicate that α‐syn was a TLRs‐mediated immunogenic agent (A53T mutant stronger than wild‐type α‐syn). The stimulation patterns suggest that persistent release and accumulation of α‐syn is required for the maintenance of innate immunity activation, and IFN‐γ expression inhibition by α‐syn suggests a novel immune molecule interaction mechanism underlying pathogenesis of neurodegenerative diseases.     

THIS ARTICLE HAS BEEN RETRACTED: Pathological biochemistry of α‐synucleinopathy

Lewy bodies (LBs) are hallmark lesions in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We raised a monoclonal antibody LB509 against purified LBs from the brains of patients with DLB that strongly immuolabled LBs, and found that α‐synuclein is one of the major components of LBs. Thus, the deposition of α‐synuclein, an abundant presynaptic brain protein, as fibrillary aggregates in affected neurons or glial cells, was highlighted as a hallmark lesion of a subset of neurodegenerative disorders, including PD, DLB and multiple system atrophy collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in and multiplication of α‐synuclein gene in some pedigrees of familial PD has strongly implicated α‐synuclein in the pathogenesis of PD and other synucleinopathies. We then examined the specific post‐translational modifications that characterize and underlie the aggregation of α‐synuclein in synucleinopathy brains by mass spectrometry and using a specific antibody, and found that serine 129 of α‐synuclein deposited in synucleinopathy lesions is selectively and extensively phosphorylated. Furthermore we generated transgenic C. elegans overexpressing α‐synuclein in neurons, and found that overexpression of familial PD‐linked mutant form of α‐synuclein impairs functions of dopamine neurons. These findings collectively underscore the importance of deposition of α‐synuclein as well as its phosphorylation in the pathogenesis of α‐synucleinopathies.     

Α‐synuclein induces microglial cell migration through stimulating HIF‐1α accumulation

Microglial cell migration and infiltration plays a critical role in spinal cord injury after thoracoabdominal aortic surgery. In our previous study, α‐synuclein, a presynaptic protein was shown to be released from injured neurons and cause microglial cell activation. Here, we aimed to explore the effect of α‐synuclein on microglial cell migration. Primary microglial cells were isolated from Sprague–Dawley rats and then exposed different doses (0.2, 0.4, and 0.6 μM) of α‐synuclein oligomers. The mRNA and protein levels of HIF‐1α were then analyzed by qRT‐PCR and Western blot. Cell migration was examined by a 96‐well Boyden chamber. Moreover, toll‐like receptor (TLR) 2‐expression as well as TLR7/8‐expression was inhibited by specific siRNA transfection. HIF‐1α was overexpressed by Ad‐HIF‐1α transfection. In the results, α‐synuclein was found to stimulate HIF‐1α accumulation in microglial cells in a dose‐dependent manner. Silencing HIF‐1α expression dampened α‐synuclein induced microglial cell migration. Furthermore, blockade of TLR7/8 expression but not TLR2 expression reduced HIF‐1α accumulation in microglial cells. In addition, overexpressed HIF‐1α, along with Src, prompted caveolin‐1 expression and phosphorylation, as well as migration in microglial cells. Α‐synuclein acts via TLR7/8 and enhances HIF‐1α expression, which might play a regulatory role in microglial cell migration. © 2017 Wiley Periodicals, Inc.     

Value of in vivo α‐synuclein deposits in Parkinson's disease: A systematic review and meta‐analysis

Previous studies that have investigated the potential of in vivo abnormal α‐synuclein deposits as a pathological biomarker for PD included few participants and reported different diagnostic accuracies. Here, we aimed to confirm the diagnostic value of in vivo α‐synuclein deposits in PD through a systematic review and meta‐analysis, with special emphasis on determining the tissue most suitable for examination and assessing whether anti‐native α‐synuclein or anti‐phosphorylated α‐synuclein antibodies should be used. Databases were searched on December 30, 2018. We finally included 41 case‐control studies that examined in vivo tissue samples using anti‐native α‐synuclein or anti‐phosphorylated α‐synuclein antibody in PD patients and controls. Using a univariate random‐effects model, pooled sensitivity and specificity (95% confidence interval) of anti‐native α‐synuclein antibody were 0.54 (0.49‐0.60) and 0.72 (0.68‐0.76) for the gastrointestinal tract and 0.76 (0.60‐0.89) and 0.60 (0.43‐0.74) for the skin. Pooled sensitivity and specificity (95% confidence interval) of anti‐phosphorylated α‐synuclein antibody were 0.43 (0.37‐0.48) and 0.82 (0.78‐0.86) for the gastrointestinal tract, 0.76 (0.69‐0.82) and 1.00 (0.98‐1.00) for the skin, 0.42 (0.26‐0.59) and 0.94 (0.84‐0.99) for the minor salivary glands, and 0.66 (0.51‐0.79) and 0.96 (0.86‐1.00) for the submandibular glands. Although ubiquitous heterogeneity between the included studies should be noted when interpreting our results, our analyses demonstrated the following: (1) in vivo α‐synuclein immunoreactivity has the potential as a pathological biomarker for PD; (2) anti‐phosphorylated α‐synuclein antibody consistently has higher specificity than anti‐native α‐synuclein antibody; and (3) skin biopsy examination using anti‐phosphorylated α‐synuclein antibody has the best diagnostic accuracy, although feasibility remains an important issue. © 2019 International Parkinson and Movement Disorder Society     

Stage‐dependent nigral neuronal loss in incidental Lewy body and Parkinson's disease

To gain a better understanding of the significance of α‐synuclein pathological conditions during disease progression in Parkinson's disease, we investigated whether 1) nigral neuronal loss in incidental Lewy body disease and Parkinson's disease donors is associated with the local burden α‐synuclein pathological conditions during progression of pathological conditions; 2) the burden and distribution of α‐synuclein pathological conditions are related to clinical measures of disease progression. Post‐mortem tissue and medical records of 24 Parkinson's disease patients, 20 incidental Lewy body disease donors, and 12 age‐matched controls were obtained from the Netherlands Brain Bank for morphometric analysis. We observed a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls. Nigral neuronal loss (12%) was already observed before the appearance α‐synuclein aggregates. The progression from Braak α‐synuclein stage 3 to 4 was associated with a significant decline in neuronal cell density (46%). Nigral neuronal loss increased with later Braak α‐synuclein stages but did not vary across consecutive Braak α‐synuclein stages. We observed a negative correlation between neuronal density and local α‐synuclein burden in the substantia nigra of Parkinson's disease patients (ρ = ?0.54), but no relationship with Hoehn & Yahr stage or disease duration. In conclusion, our findings cast doubt on the pathogenic role of α‐synuclein aggregates in elderly, but do suggest that the severity of neurodegeneration and local burden of α‐synuclein pathological conditions are closely coupled during disease progression in Parkinson's disease. © 2014 International Parkinson and Movement Disorder Society     

Tau/α‐synuclein ratio and inflammatory proteins in Parkinson's disease: An exploratory study

Background : No CSF or plasma biomarker has been validated for diagnosis or progression of PD. Objectives : To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity. Methods : CSF levels of α‐synuclein, amyloid‐ß1‐42, total tau, and threonine‐181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin‐1ß, interleukin‐2, interleukin, interferon‐γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort. Results : CSF levels of α‐synuclein, amyloid‐ß1‐42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α‐synuclein, phosphorylated tau/α‐synuclein, total tau/amyloid‐ß1‐42+α‐synuclein, and phosphorylated tau/amyloid‐ß1‐42+α‐synuclein ratios were higher in patients. The best area under the curve value was obtained for the phosphorylated tau/α‐synuclein ratio alone (0.86) and also when this was combined with tumor necrosis factor α in CSF (0.91; sensitivity 92.9%, specificity 75% for a cut‐off value of ≤ 0.71). Phosphorylated tau/α‐synuclein and phosphorylated tau/amyloid‐ß1‐42+α‐synuclein were higher in patients than in controls of the Parkinson's Progression Markers Initiative database. Plasma cytokines did not differ between groups, although interleukin‐6 levels were positively correlated with UPDRS‐I, ‐II, and ‐III scores. Conclusions : The CSF phosphorylated tau/α‐synuclein ratio alone, and in combination with tumor necrosis factor α and plasma interleukin‐6 levels, might serve as biomarkers to diagnose PD and monitor its severity. © 2017 International Parkinson and Movement Disorder Society     

Dopamine and Cu+/2+ can induce oligomerization of α‐synuclein in the absence of oxygen: Two types of oligomerization mechanisms for α‐synuclein and related cell toxicity studies

α‐Synuclein oligomers can induce neurotoxicity and are implicated in Parkinson's disease etiology and disease progression. Many studies have reported α‐synuclein oligomerization by dopamine (DA) and transition metal ions, but few studies provide insight into joint influences of DA and Cu²⁺. In this study, DA and Cu²⁺ were coadministered aerobically to measure α‐synuclein oligomerization under these conditions. In the presence of oxygen, DA induced α‐synuclein oligomerization in a dose‐dependent manner. Cu^+/2+ did not effect oligomerization in such a manner in the presence of DA. By electrophoresis, Cu²⁺ was found easily to induce oligomerization with DA. This implies that oligomerization invoked by DA is reversible in the presence of Cu²⁺, which appears to be mediated by noncovalent bond interactions. In the absence of oxygen, DA induced less oligomerization of α‐synuclein, whereas DA/Cu²⁺ induced aerobic‐level amounts of oligomers, suggesting that DA/Cu²⁺ induces oligomerization independent of oxygen concentration. Radical species were detected through electron paramagnetic resonance (EPR) spectroscopic analysis arising from coincubation of DA/Cu²⁺ with α‐synuclein. Redox reactions induced by DA/Cu²⁺ were observed in multimer regions of α‐synuclein oligomers through NBT assay. Cellular toxicity results confirm that, for normal and hypoxic conditions, copper or DA/Cu²⁺ can induce cell death, which may arise from copper redox chemistry. From these results, we propose that DA and DA/Cu²⁺ induce different mechanisms of α‐synuclein oligomerization, cross‐linking with noncovalent (or reversible covalent) bonding vs. likely radical‐mediated covalent modification. © 2013 Wiley Periodicals, Inc.     

Upregulation of α‐synuclein expression in the rat cerebellum in experimental hepatic encephalopathy

I. Suárez, G. Bodega and B. Fernández (2010) Neuropathology and Applied Neurobiology 36, 422–435
Upregulation of α‐synuclein expression in the rat cerebellum in experimental hepatic encephalopathy Aims: The overexpression of α‐synuclein has been associated with neurodegenerative diseases, especially when the protein aggregates to form insoluble structures. The present study examined the effect of chronic hyperammonaemia on α‐synuclein expression in the rat cerebellum following portacaval anastomosis (PCA). Methods: Immunohistochemical and western blot determinations were performed 1 month and 6 months after the PCA procedure. Results: A time‐dependent increase in α‐synuclein expression was seen in the cerebellar grey matter compared with the controls. At 1 month post PCA, α‐synuclein‐immunopositive material was observed in the molecular layer, while the Purkinje cells showed weak α‐synuclein expression, and α‐synuclein aggregates were observed throughout the granular layer. At 6 months post PCA, α‐synuclein expression was significantly increased compared with the controls. α‐synuclein‐immunostained astroglial cells were also found; the Bergmann glial cells showed α‐synuclein‐positive processes in the molecular layer of PCA‐exposed rats, and in the granular layer, perivascular astrocytes showed intense α‐synuclein immunoreactivity, as indicated by colocalization of α‐synuclein with glial fibrillary acidic protein (GFAP). In addition, ubiquitin‐immunoreactive inclusions were present in PCA‐exposed rats, although they did not colocalize with α‐synuclein. Western blotting performed at 6 months post PCA showed a reduction in the level of soluble α‐synuclein compared with 1 month post PCA and the controls; this reduction was concomitant with an increase in the insoluble form of α‐synuclein. Conclusions: Although the precise mechanism by which α‐synuclein aggregates in PCA‐treated rats remains unknown, the present data suggest an important role for this protein in the onset and progression of hepatic encephalopathy, probably via its expression in astroglial cells.     

Multiple system atrophy: α‐synuclein and neuronal degeneration

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that encompasses olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy–Drager syndrome (SDS). The histopathological hallmark is the formation of α‐synuclein‐positive glial cytoplasmic inclusions (GCIs) in oligodendroglia. α‐synuclein aggregation is also found in glial nuclear inclusions, neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurites. We evaluated the pathological features of 102 MSA cases, and presented the pathological spectrum of MSA and initial features of α‐synuclein accumulation. We found that 39% of the 102 cases showed equivalent SND and OPCA pathologies, 33% showed OPCA‐ and 22% showed SND‐predominant pathology, whereas 6% showed extremely mild changes. Our pathological analysis indicated that OPCA‐type was relatively more frequent and SND‐type was less frequent in Japanese MSA cases, compared to the relatively high frequency of SND‐type in Western countries, suggesting that different phenotypic patterns of MSA may exist between races. In the early stage, in addition to GCIs, NNIs and diffuse homogenous α‐synuclein staining in neuronal nuclei and cytoplasm were observed in lesions in the pontine nuclei, putamen, substantia nigra, locus ceruleus, inferior olivary nucleus, intermediolateral column of thoracic spinal cord, lower motor neurons and cortical pyramidal neurons. A subgroup of MSA cases with severe temporal atrophy showed numerous NCIs, particularly in the limbic system. These findings suggest that primary non‐fibrillar and fibrillar α‐synuclein aggregation also occur in neurons. The oligo‐myelin‐axon‐neuron complex mechanism, along with the direct involvement of neurons themselves, may synergistically accelerate the degenerative process of MSA.     

Glycogen synthase kinase‐3β phosphorylates synphilin‐1 in vitro

α‐Synuclein is known to be a major component of Lewy bodies and glial cytoplasmic inclusions in the brains of patients with α‐synucleinopathies. Synphilin‐1, an α‐synuclein‐associated protein, is also present in these inclusions. However, little is known about the post‐translational modifications of synphilin‐1. In the present study, it is reported that synphilin‐1 is phosphorylated by glycogen synthase kinase‐3βin vitro. It is well known that protein phosphorylation is involved in various physiological phenomena, including signal transduction and protein degradation. Therefore, phosphorylation of synphilin‐1 may play an important role in the function of this protein in the brain.     

Tau‐positive glial cytoplasmic granules in multiple system atrophy

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease that is pathologically characterized by the filamentous aggregation of α‐synuclein. We report a case of MSA showing unusual neuropathological findings and review six autopsied cases of MSA. The patient progressively developed parkinsonism and ataxia for the 9 years prior to her death at the age of 72 years. Neuropathological examinations revealed neuronal loss restricted to the olivopontocerebellar and striatonigral region, which was more severe in the putamen. Staining with anti‐α‐synuclein antibody demonstrated widespread occurrence of glial cytoplasmic inclusions, which mainly accumulated in oligodendroglial cells and corresponded closely to the degree of disease progression. In addition, tau‐positive granules were detected within the glial cytoplasm in the neurodegenerative region, which was especially prominent in the putamen and internal capsule. Tau accumulation was also clearly recognized by staining with specific antibodies against three‐repeat or four‐repeat tau. The glia that demonstrated deposition of tau‐positive granules were distinguished from α‐synuclein‐positive oligodendroglia by double immunohistochemical staining. These characteristic glial accumulations of tau were also present in all six cases of MSA. These results indicate that tau‐positive granules in glia are common findings in MSA and that tau aggregation might be another pathway to neurodegeneration in MSA.