Viral‐mediated oligodendroglial alpha‐synuclein expression models multiple system atrophy

Background : MSA is a fatal neurodegenerative disorder characterized by a combination of autonomic dysfunction, cerebellar ataxia, and l ‐dopa unresponsive parkinsonism. The hallmark of MSA is the accumulation of α‐synuclein, forming cytoplasmic inclusions in oligodendrocytes. Adeno‐associated viruses allow efficient targeting of disease‐associated genes in selected cellular ensembles and have proven efficient for the neuronal overexpression of α‐synuclein in the substantia nigra in the context of PD. Objectives : We aimed to develop viral‐based models of MSA. Methods : Chimeric viral vectors expressing either human wild‐type α‐synuclein or green fluorescent protein under the control of mouse myelin basic protein were injected in the striatum of rats and monkeys. Rats underwent a longitudinal motor assessment before histopathological analysis at 3 and 6 months. Results : Injection of vectors expressing α‐synuclein in the striatum resulted in >80% oligodendroglial selectivity in rats and >60% in monkeys. Rats developed progressive motor deficits that were l ‐dopa unresponsive when assessed at 6 months. Significant loss of dopaminergic neurons occurred at 3 months, further progressing at 6 months, together with a loss of striatal neurons. Prominent α‐synuclein accumulation, including phosphorylated and proteinase‐K–resistant α‐synuclein, was detected in the striatum and substantia nigra. Conclusions : Viral‐mediated oligodendroglial expression of α‐synuclein allows replicating some of the key features of MSA. This flexible strategy can be used to investigate, in several species, how α‐synuclein accumulation in selected oligodendroglial populations contributes to the pathophysiology of MSA and offers a new framework for preclinical validation of therapeutic strategies. © 2017 International Parkinson and Movement Disorder Society     

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.     

Accumulation of phosphorylated α‐synuclein in subpial and periventricular astrocytes in multiple system atrophy of long duration

The histological hallmark of multiple system atrophy (MSA) is accumulation of phosphorylated α‐synuclein in oligodendrocytes. However, it is uncertain whether phosphorylated α‐synuclein accumulates in astrocytes of MSA patients. We immunohistochemically examined the frontal and temporal lobes, basal ganglia, cerebellum, brainstem and spinal cord of patients with MSA (n = 15) and Lewy body disease (n = 20), and also in control subjects (n = 20). Accumulation of abnormally phosphorylated and aggregated α‐synuclein was found in subpial and periventricular astrocytes in six of the 15 patients with MSA (40%). The structures were confined to the subpial surface of the ventro‐lateral part of the spinal cord and brainstem, as well as the subependymal region of the lateral ventricles. They were not visualized by Gallyas‐Braak staining, and were immunonegative for ubiquitin and p62. Immunoelectron microscopy revealed that the phosphorylated α‐synuclein‐immunoreactive structures in astrocytes were non‐fibrillar and associated with granular and vesicular structures. The extent of phosphorylated α‐synuclein‐immunoreactive astrocytes was correlated with disease duration. No such structures were found in Lewy body disease or controls. Accumulation of phosphorylated α‐synuclein can occur in subpial and periventricular astrocytes in patients with MSA, especially in those with a long disease duration.     

Somatic sprouts of the Purkinje cells in a patient with multiple system atrophy

We describe the post mortem case of a 71‐year‐old Japanese woman diagnosed as having multiple system atrophy (MSA), showing somatic sprouting formation of Purkinje cells. The patient had suffered from frequent falling episodes and clumsiness of the left hand since the age of 67 years. Orthostatic hypotension and parkinsonism subsequently emerged. Typical neuropathological features of MSA, including degeneration of the striatum, pontine base and cerebellum with abundance of phosphorylated α‐synuclein‐positive neuronal and glial cytoplasmic and nuclear inclusions in the brain, were observed. In addition to gliosis of the cerebellar white matter and notable loss of Purkinje cells, several Purkinje cells showed somatic sprouting. Somatic sprouting of Purkinje cells has been demonstrated in several specific conditions, such as developing brains and several neurodegenerative disorders, including Menkes kinky hair disease, familial spinocerebellar ataxia, acute encephalopathy linked to familial hemiplegic migraine, and Huntington’s disease; however, no MSA cases have been reported with sprouting from the soma of Purkinje cells. Axonal damage caused by oligodendroglial dysfunction could be crucial in the development of Purkinje cell loss in MSA. Moreover, no apparent α‐synuclein accumulation has been described in the Purkinje cells of MSA. We propose that MSA is another degenerative disorder associated with somatic sprouts of Purkinje cells.     

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.     

Nigral burden of α‐synuclein correlates with striatal dopamine deficit

Aggregated α‐synuclein is the hallmark of Parkinson's disease (PD), diffuse Lewy body disease (DLBD), and multiple system atrophy (MSA). Physiologically, α‐synuclein ensures normal functions of dopamine transporter (DAT) and tyrosine hydoxylase. In α‐synucleinopathies, it accumulates in neuronal cytoplasm and neurites through several stages. It is unclear whether the accumulation of pathological α‐synuclein in the substantia nigra in PD correlates with the dopaminergic deficit in the striatal target. We evaluated the impact of the nigral burden of pathological α‐synuclein immunoreactivity in 27 α‐synucleinopathy brains by morphometric immunohistochemistry. DAT immunoreactivity in the striatum inversely correlates with the total α‐synuclein burden in the substantia nigra but not with cytoplasmic inclusion counts only. This result has implications for imaging, clinicopathological correlative studies, and staging of the disease process. © 2008 Movement Disorder Society     

Definite familial multiple system atrophy with unknown genetics

Multiple system atrophy (MSA) is an oligodendrogliopathy of presumably sporadic origin, characterized by prominent α‐synuclein inclusions with neuronal multisystem degeneration, although a few Mendelian pedigrees have been reported. Here we report two familial cases of MSA of unknown genetic background. One patient was diagnosed as a possible MSA‐C (cerebellar dysfuntion) case, and the other as clinically possible MSA‐P (parkinsonism), which turned out to be definite MSA, based on a detailed autopsy. The neuropathology showed extensive deposition of α‐synuclein in the glia as well as in the neurons located in the cerebral cortices and hippocampal systems, although neither multiplication of the SNCA gene or mutations in COQ2 gene were identified in the family concerned.     

Multiple System Atrophy: Recent Developments and Future Perspectives

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by a variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction. The pathologic hallmark is the accumulation of aggregated α‐synuclein in oligodendrocytes, forming glial cytoplasmic inclusions, which qualifies MSA as a synucleinopathy together with Parkinson's disease and dementia with Lewy bodies. The underlying pathogenesis is still not well understood. Some symptomatic treatments are available, whereas neuroprotection remains an urgent unmet treatment need. In this review, we critically appraise significant developments of the past decade with emphasis on pathogenesis, diagnosis, prognosis, and treatment development. We further discuss unsolved questions and highlight some perspectives. © 2019 International Parkinson and Movement Disorder Society     

Fluorescence and autoradiographic evaluation of tau PET ligand PBB3 to α‐synuclein pathology

Background : The tau PET ligand 2‐((1E,3E)‐4‐(6‐([¹¹C]methylamino)pyridin‐3‐yl)buta‐1,3‐dienyl)benzo[d]thiazol‐6‐ol ([¹¹C]PBB3) binds to a wide range of tau pathology; however, binding property of PBB3 to non‐tau inclusions remains unknown. To clarify whether [¹¹C]PBB3 binds to α‐synuclein pathology, reactivity of PBB3 was assessed by in vitro fluorescence and autoradiographic labeling of brain sections from α‐synucleinopathies patients. Method : Of 10 pure Lewy body disease and 120 multiple system atrophy (MSA) cases in the Mayo Clinic brain bank, we selected 3 Lewy body disease and 4 MSA cases with a range of α‐synuclein severity based on the quantitative analysis of α‐synuclein burden. PBB3 fluorescence labeling, double or single immunostaining for α‐synuclein and phospho‐tau, Prussian blue staining, and in vitro autoradiography with [¹¹C]PBB3 were performed for these selected samples. Results : PBB3 fluorescence labeled various α‐synuclein lesions including Lewy bodies, Lewy neurites, spheroids, glial cytoplasmic inclusions, and neuronal cytoplasmic inclusions. Meanwhile, autoradiographic labeling with [¹¹C]PBB3 at 10 nM demonstrated no significant binding in Lewy body disease cases. In contrast, significant autoradiographic binding of [¹¹C]PBB3 to the striatopallidal fibers was found in 2 MSA cases, which had high densities of glial cytoplasmic inclusions without tau or iron deposits in this region. Conclusions : Given that the maximum concentration of [¹¹C]PBB3 in human PET scans is approximately 10 nM, the present data imply that α‐synuclein pathology in Lewy body disease is undetectable by [¹¹C]PBB3‐PET, whereas those in a subset of MSA cases with high densities of glial cytoplasmic inclusions could be captured by this radioligand. © 2017 International Parkinson and Movement Disorder Society     

α‐Synuclein pathology in the cranial and spinal nerves in Lewy body disease

Accumulation of phosphorylated α‐synuclein in neurons and glial cells is a histological hallmark of Lewy body disease (LBD) and multiple system atrophy (MSA). Recently, filamentous aggregations of phosphorylated α‐synuclein have been reported in the cytoplasm of Schwann cells, but not in axons, in the peripheral nervous system in MSA, mainly in the cranial and spinal nerve roots. Here we conducted an immunohistochemical investigation of the cranial and spinal nerves and dorsal root ganglia of patients with LBD. Lewy axons were found in the oculomotor, trigeminal and glossopharyngeal‐vagus nerves, but not in the hypoglossal nerve. The glossopharyngeal‐vagus nerves were most frequently affected, with involvement in all of 20 subjects. In the spinal nerve roots, Lewy axons were found in all of the cases examined. Lewy axons in the anterior nerves were more frequent and numerous in the thoracic and sacral segments than in the cervical and lumbar segments. On the other hand, axonal lesions in the posterior spinal nerve roots appeared to increase along a cervical‐to‐sacral gradient. Although Schwann cell cytoplasmic inclusions were found in the spinal nerves, they were only minimal. In the dorsal root ganglia, axonal lesions were seldom evident. These findings indicate that α‐synuclein pathology in the peripheral nerves is axonal‐predominant in LBD, whereas it is restricted to glial cells in MSA.     

Cellular pathology in multiple system atrophy

Multiple system atrophy (MSA) is a sporadic, adult‐onset neurodegenerative disease, which is characterized by striatonigral degeneration, olivopontocerebellar atrophy, and preganglionic autonomic lesions in any combination. The histological hallmark is the presence of argyrophilic fibrillary inclusions in the oligodendrocytes, referred to as glial cytoplasmic inclusions (GCIs). Fibrillary inclusions are also found in the neuronal somata, axons, and nucleus. Neuronal cytoplasmic inclusions are frequently found in the pontine and inferior olivary nuclei. Since the discovery of α‐synuclein as a major component of glial and neuronal inclusions in MSA, two neurodegenerative processes have been considered in this disease: one is due to the widespread occurrence of GCIs associated with oligodendroglia–myelin degeneration (oligodendrogliopathy) in the central nervous system, and the other is due to the filamentous aggregation of α‐synuclein in the neurons in several brain regions. These two degenerative processes might synergistically cause neuronal depletion in MSA.     

Isopentenyl diphosphate isomerase,a cholesterol synthesizing enzyme,is localized in Lewy bodies

Isopentenyl diphosphate isomerase (IDI) is a cytoplasmic enzyme involved in the biosynthesis of isoprenoids including cholesterols. IDI has two isoforms in humans: IDI1 and IDI2. Since lipids are known to be a component of Lewy bodies (LBs), we investigated the immunohistochemical localization of IDI1 and IDI2 in the brain of patients with LB disease and multiple system atrophy (MSA) and normal control subjects. In normal controls, the cytoplasm of neurons was weakly immunostained with anti‐IDI1 and anti‐IDI2 antibodies throughout the nervous system. In LB disease, brainstem‐type LBs were strongly positive for IDI1 and IDI2, and cortical LBs were unstained or barely immunolabeled. Double immunofluorescence staining revealed co‐localization of phosphorylated α‐synuclein with IDI1 or IDI2. Glial cytoplasmic inclusions in MSA were unstained. Previous studies have shown that levels of cholesterol metabolites are increased in the cerebral cortex of patients with LB disease, and that these metabolites accelerate α‐synuclein aggregation. The present findings suggest that IDI1 and IDI2 may be associated with the production of cholesterol metabolites in neurons, leading to α‐synuclein aggregation during the process of LB formation.     

Bladder dysfunction in a transgenic mouse model of multiple system atrophy

Multiple system atrophy (MSA) is an adult‐onset neurodegenerative disorder presenting with motor impairment and autonomic dysfunction. Urological function is altered in the majority of MSA patients, and urological symptoms often precede the motor syndrome. To date, bladder function and structure have never been investigated in MSA models. We aimed to test bladder function in a transgenic MSA mouse featuring oligodendroglial α‐synucleinopathy and define its applicability as a preclinical model to study urological failure in MSA. Experiments were performed in proteolipid protein (PLP)–human α‐synuclein (hαSyn) transgenic and control wild‐type mice. Diuresis, urodynamics, and detrusor strip contractility were assessed to characterize the urological phenotype. Bladder morphology and neuropathology of the lumbosacral intermediolateral column and the pontine micturition center (PMC) were analyzed in young and aged mice. Urodynamic analysis revealed a less efficient and unstable bladder in MSA mice with increased voiding contraction amplitude, higher frequency of nonvoiding contractions, and increased postvoid residual volume. MSA mice bladder walls showed early detrusor hypertrophy and age‐related urothelium hypertrophy. Transgenic hαSyn expression was detected in Schwann cells ensheathing the local nerve fibers in the lamina propria and muscularis of MSA bladders. Early loss of parasympathetic outflow neurons and delayed degeneration of the PMC accompanied the urological deficits in MSA mice. PLP‐hαSyn mice recapitulate major urological symptoms of human MSA that may be linked to αSyn‐related central and peripheral neuropathology and can be further used as a preclinical model to decipher pathomechanisms of MSA. © 2013 Movement Disorder Society     

Review: Novel treatment strategies targeting alpha‐synuclein in multiple system atrophy as a model of synucleinopathy

Neurodegenerative disorders with alpha‐synuclein (α‐syn) accumulation (synucleinopathies) include Parkinson's disease (PD), PD dementia, dementia with Lewy bodies and multiple system atrophy (MSA). Due to the involvement of toxic α‐syn aggregates in the molecular origin of these disorders, developing effective therapies targeting α‐syn is a priority as a disease‐modifying alternative to current symptomatic treatments. Importantly, the clinical and pathological attributes of MSA make this disorder an excellent candidate as a synucleinopathy model for accelerated drug development. Recent therapeutic strategies targeting α‐syn in in vivo and in vitro models of MSA, as well as in clinical trials, have been focused on the pathological mechanisms of α‐syn synthesis, aggregation, clearance, and/or cell‐to‐cell propagation of its neurotoxic conformers. Here we summarize the most relevant approaches in this direction, with emphasis on their potential as general synucleinopathy modifiers, and enumerate research areas for potential improvement in MSA drug discovery.     

Lysosomal trafficking defects link Parkinson's disease with Gaucher's disease

Lysosomal dysfunction has been implicated in multiple diseases, including lysosomal storage disorders such as Gaucher's disease, in which loss‐of‐function mutations in the GBA1 gene encoding the lysosomal hydrolase β‐glucocerebrosidase result in lipid substrate accumulation. In Parkinson's disease, α‐synuclein accumulates in Lewy bodies and neurites contributing to neuronal death. Previous clinical and genetic evidence has demonstrated an important link between Parkinson's and Gaucher's disease, as GBA1 mutations and variants increase the risk of Parkinson's and Parkinson's patients exhibit decreased β‐glucocerebrosidase activity. Using human midbrain neuron cultures, we have found that loss of β‐glucocerebrosidase activity promotes α‐synuclein accumulation and toxicity, whereas α‐synuclein accumulation further contributes to decreased lysosomal β‐glucocerebrosidase activity by disrupting β‐glucocerebrosidase trafficking to lysosomes. Moreover, α‐synuclein accumulation disrupts trafficking of additional lysosomal hydrolases, further contributing to lysosomal dysfunction and neuronal dyshomeostasis. Importantly, promoting β‐glucocerebrosidase activity reduces α‐synuclein accumulation and rescues lysosomal and neuronal dysfunction, suggesting that β‐glucocerebrosidase may be an important therapeutic target for advancing drug discovery in synucleinopathies including Parkinson's disease. © 2016 International Parkinson and Movement Disorder Society.     

Parkinson's disease,cortical dysfunction,and alpha‐synuclein

The ability to understand how Parkinson's disease neurodegeneration leads to cortical dysfunction will be critical for developing therapeutic advances in Parkinson's disease dementia. The overall purpose of this project was to study the small‐amplitude cortical myoclonus in Parkinson's disease as an in vivo model of focal cortical dysfunction secondary to Parkinson's disease neurodegeneration. The objectives were to test the hypothesis that cortical myoclonus in Parkinson's disease is linked to abnormal levels of α‐synuclein in the primary motor cortex and to define its relationship to various biochemical, clinical, and pathological measures. The primary motor cortex was evaluated for 11 Parkinson's disease subjects with and 8 without electrophysiologically confirmed cortical myoclonus (the Parkinson's disease + myoclonus group and the Parkinson's disease group, respectively) who had premortem movement and cognitive testing. Similarly assessed 9 controls were used for comparison. Measurements for α‐synuclein, Aβ‐42 peptide, and other biochemical measures were made in the primary motor cortex. A 36% increase in α‐synuclein was found in the motor cortex of Parkinson's disease + myoclonus cases when compared with Parkinson's disease without myoclonus. This occurred without significant differences in insoluble α‐synuclein, phosphorylated to total α‐synuclein ratio, or Aβ‐42 peptide levels. Higher total motor cortex α‐synuclein levels significantly correlated with the presence of cortical myoclonus but did not correlate with multiple clinical or pathological findings. These results suggest an association between elevated α‐synuclein and the dysfunctional physiology arising from the motor cortex in Parkinson's disease + myoclonus cases. Alzheimer's disease pathology was not associated with cortical myoclonus in Parkinson's disease. Cortical myoclonus arising from the motor cortex is a model to study cortical dysfunction in Parkinson's disease. © 2011 Movement Disorder Society     

TDP-43 pathology occurs infrequently in multiple system atrophy

F. Geser, J. A. Malunda, H. I. Hurtig, J. E. Duda, G. K. Wenning, S. Gilman, P. A. Low, V. M.‐Y. Lee and J. Q. Trojanowski (2011) Neuropathology and Applied Neurobiology 37, 358–365
TDP‐43 pathology occurs infrequently in multiple system atrophy Aims and Methods: The α‐synucleinopathy multiple system atrophy (MSA) and diseases defined by pathological 43‐kDa transactive response DNA‐binding protein (TDP‐43) or fused in sarcoma (FUS) aggregates such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration show overlapping clinico‐pathological features. Consequently, we examined MSA for evidence of TDP‐43 or FUS pathology utilizing immunohistochemical studies in autopsy material from 29 MSA patients. Results: TDP‐43 pathology was generally rare, and there were no FUS lesions. The TDP‐43 lesions were located predominantly in medio‐temporal lobe and subcortical brain areas and were comprised mainly of dystrophic processes and perivascular (and subpial) lesions. Conclusions: The multisystem clinical symptoms and signs of MSA, and in particular the neurobehavioural/cognitive and pyramidal features, appear not to result from concomitant TDP‐43 or FUS pathology, but rather from widespread white matter α‐synuclein positive glial cytoplasmic inclusions and neurodegeneration in keeping with a primary α‐synuclein‐mediated oligodendrogliopathy. The gliodegenerative disease MSA evidently results from different pathogenetic mechanisms than neurodegenerative diseases linked to pathological TDP‐43.     

Lysosomal Dysfunction and α‐Synuclein Aggregation in Parkinson's Disease: Diagnostic Links

Lysosomal impairment is increasingly recognized as a central event in the pathophysiology of PD. Genetic associations between lysosomal storage disorders, including Gaucher disease and PD, highlight common risk factors and pathological mechanisms. Because the autophagy–lysosomal system is involved in the intralysosomal hydrolysis of dysfunctional proteins, lysosomal impairment may contribute to α‐synuclein aggregation in PD. The degradation of α‐synuclein is a complex process involving different proteolytic mechanisms depending on protein burden, folding, posttranslational modifications, and yet unknown factors. In this review, evidence for lysosomal dysfunction in PD and its intimate relationship with α‐synuclein aggregation are discussed, after which the question of whether lysosomal proteins may serve as diagnostic biomarkers for PD is addressed. Changes in lysosomal enzymes, such as reduced glucocerebrosidase and cathepsin levels, have been observed in affected brain regions in PD patients. The detection of lysosomal proteins in CSF may provide a read‐out of lysosomal dysfunction in PD and holds promise for the development of diagnostic PD biomarkers. Initial PD biomarker studies demonstrated altered lysosomal enzyme activities in CSF of PD patients when compared with controls. However, CSF lysosomal enzyme activities alone could not discriminate between PD patients and controls. The combination of CSF lysosomal markers with α‐synuclein species and indicators of mitochondrial dysfunction, inflammation, and other pathological proteins in PD may be able to facilitate a more accurate diagnosis of PD. Further CSF biomarker studies are needed to investigate the utility of CSF lysosomal proteins as measures of disease state and disease progression in PD. © 2016 International Parkinson and Movement Disorder Society     

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.     

Neuropathology of multiple system atrophy: New thoughts about pathogenesis

Multiple system atrophy (MSA) is a fatal adult‐onset neurodegenerative disorder of uncertain etiology, clinically manifesting with autonomic failure associated with parkinsonism, cerebellar dysfunction, and pyramidal signs in variable combination. The pathological process affects central autonomic, striatonigral, and olivopontocerebellar systems. These show varying degrees of neurodegeneration and underlie the stratification of the heterogenous disorder into MSA‐P and MSA‐C clinical variants, which correlate to the morphologic phenotypes of striatonigral degeneration and olivopontocerebellar atrophy (MSA‐C). The lesions are not limited to these most consistently and severely affected systems but may involve many other parts of the central, peripheral, and autonomic nervous systems, underpinning the multisystem character of MSA. The histological core feature are glial cytoplasmic inclusions (GCIs, Papp‐Lantos bodies) in all types of oligodendroglia that contain aggregates of misfolded α‐Synuclein (α‐Syn). In addition to the ectopic appearance of α‐Syn in oligodendrocytes and other cells, oxidative stress, proteasomal and mitochondrial dysfunction, excitotoxiciy, neuroinflammation, metabolic changes, and energy failure are important contributors to the pathogenesis of MSA, as shown by various neurotoxic and transgenic animal models. Although the basic mechanisms of α‐Syn–triggered neurodegeneration are not completely understood, neuron‐to‐oligodendrocyte transfer of α‐Syn by prion‐like spreading, inducing oligodendroglial and myelin dysfunction associated with chronic neuroinflammation, are suggested finally to lead to a system‐specific pattern of neurodegeneration. © 2014 International Parkinson and Movement Disorder Society