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Brain Pathology (Zurich, Switzerland) May 2023The pathological hallmark of multiple system atrophy (MSA) is aberrant accumulation of phosphorylated α-synuclein in oligodendrocytes, forming glial cytoplasmic...
Early and extensive alterations of glial connexins, distal oligodendrogliopathy type demyelination, and nodal/paranodal pathology are characteristic of multiple system atrophy.
The pathological hallmark of multiple system atrophy (MSA) is aberrant accumulation of phosphorylated α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions (GCIs). Extensive demyelination occurs particularly in the olivopontocerebellar and striatonigral pathways, but its precise mechanism remains elusive. Glial connexins (Cxs), which form gap junction channels between astrocytes and oligodendrocytes, play critical roles in myelin maintenance, and have not been studied in MSA. Therefore, we immunohistochemically investigated glial Cx changes in the cerebellar afferent fibers in 15 autopsied patients with MSA. We classified demyelinating lesions into three stages based on Klüver-Barrera staining: early (Stage I), intermediate (Stage II), and late (Stage III) stages showing subtle, moderate, and severe myelin reduction, respectively. Myelin-associated glycoprotein, but not myelin oligodendrocyte glycoprotein, was preferentially decreased in Stage I, suggesting distal oligodendrogliopathy type demyelination. Accumulation of phosphorylated α-synuclein in oligodendrocytes was frequently seen in Stage I but less frequently observed in Stages II and III. Tubulin polymerization-promoting protein (TPPP/p25α)-positive oligodendrocytes were preserved in Stage I but successively decreased in Stages II and III. Even at Stage I, Cx32 was nearly absent from myelin, despite the relative preservation of other nodal proteins, such as neurofascin, claudin-11/oligodendrocyte-specific protein, and contactin-associated protein 1, which successively decreased in the later stages. Cx32 was re-distributed in the oligodendrocyte cytoplasm and co-localized with GCIs. Cx47 gradually decreased at the oligodendrocyte surface in a stage-dependent manner but was not co-localized with GCIs. Astrocytic Cx43 was down-regulated in Stage I but up-regulated in Stages II and III, reflecting astrogliosis. Cx43/Cx47 gap junctions significantly decreased from Stage I to III. Activated microglia/macrophages and T cells infiltrated in Stage I rather than Stages II and III. Therefore, early and extensive alterations of glial Cxs, particularly Cx32 loss, occur in MSA and may accelerate distal oligodendrogliopathy type demyelination and nodal/paranodal dysfunction through disruption of inter-glial communication.
Topics: Humans; Connexins; Connexin 43; alpha-Synuclein; Multiple System Atrophy; Demyelinating Diseases
PubMed: 36368713
DOI: 10.1111/bpa.13131 -
Frontiers in Neurology 2020Spinocerebellar ataxia type 3 (SCA) is a cerebellum-dominant degenerative disorder that is characterized primarily by infratentorial damage, although less severe...
Spinocerebellar ataxia type 3 (SCA) is a cerebellum-dominant degenerative disorder that is characterized primarily by infratentorial damage, although less severe supratentorial involvement may contribute to the clinical manifestation. These impairments may result from the efferent loss of the cerebellar cortex and degeneration of the cerebral cortex. We used the three-dimensional fractal dimension (3D-FD) method to quantify the morphological changes in the supratentorial regions and assessed atrophy in the relatively focal regions in patients with SCA3. A total of 48 patients with SCA3 and 50 sex- and age-matched healthy individuals, as the control group, participated in this study. The 3D-FD method was proposed to distinguish 97 automatic anatomical label regions of gray matter (left cerebrum: 45, right cerebrum: 45, cerebellum: 7) between healthy individuals and patients with SCA3. Patients with SCA3 exhibited reduced brain complexity within both the traditional olivopontocerebellar atrophy (OPCA) pattern and specific supratentorial regions. The study results confirmed the extensive involvement of extracerebellar regions in SCA3. The atrophied regions of SCA3 in infratentorial and supratentorial cortex showed a wide range of overlapped areas as in two functional cortexes, namely cerebellum-related cortex and basal ganglia-related cortex. Our results found that the atrophy of the SCA3 are not only limited in the infratentorial regions. Both cerebellar related cortex and basal ganglia related cortex were affected in the disease process of SCA3. Our findings might correlate to the common symptoms of SCA3, such as ataxia, Parkinsonism, dysarthria, and dysmetria. SCA3 should no longer be considered a disease limited to the cerebellum and its connections; rather, it should be considered a pathology affecting the whole brain.
PubMed: 32194495
DOI: 10.3389/fneur.2020.00124 -
Movement Disorders : Official Journal... Feb 2023Somatic α-synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains.
BACKGROUND
Somatic α-synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains.
OBJECTIVE
The aim was to compare somatic SNCA CNVs in MSA subtypes (striatonigral degeneration [SND] and olivopontocerebellar atrophy [OPCA]) and correlate with inclusions.
METHODS
We combined fluorescent in situ hybridization with immunofluorescence for α-synuclein and in some cases oligodendrocyte marker tubulin polymerization promoting protein (TPPP).
RESULTS
We analyzed one to three brain regions from 24 MSA cases (13 SND, 11 OPCA). In a region preferentially affected in one subtype (putamen in SND, cerebellum in OPCA), mosaicism was higher in that subtype, and cells with CNVs were 4.2 times more likely to have inclusions. In the substantia nigra, nonpigmented cells with CNVs and TPPP were about six times more likely to have inclusions.
CONCLUSIONS
The correlation between SNCA CNVs and pathology (at a regional level) and inclusions (at a single-cell level) suggests a role for somatic SNCA CNVs in MSA pathogenesis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Multiple System Atrophy; alpha-Synuclein; DNA Copy Number Variations; In Situ Hybridization, Fluorescence; Olivopontocerebellar Atrophies
PubMed: 36448620
DOI: 10.1002/mds.29291 -
Movement Disorders : Official Journal... Nov 2021Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by aggregated α-synuclein (α-syn) in oligodendrocytes and accompanied by...
BACKGROUND
Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by aggregated α-synuclein (α-syn) in oligodendrocytes and accompanied by striatonigral and olivopontocerebellar degeneration and motor symptoms. Key features of MSA are replicated in the PLP-α-syn transgenic mouse, including progressive striatonigral degeneration and motor deterioration. There are currently no approved treatments for MSA. ATH434 is a novel, orally bioavailable brain penetrant small molecule inhibitor of α-syn aggregation.
OBJECTIVES
To characterize ATH434 for disease modification in a mouse model of MSA.
METHODS
Six-month-old PLP-α-syn mice (MSA mice) were ATH434-treated (ATH434 in food) or untreated (normal food) for 6 months. Motor behavior and numbers of nigral and striatal neurons were evaluated. α-syn aggregates and oligomers were quantified by immunohistochemical and western blot analyses. Microglial activation and neuroinflammation were assessed by histological and molecular analyses. Ferric iron in the Substantia nigra was evaluated with the Perls method.
RESULTS
ATH434-treated mice demonstrated preservation of motor performance in MSA mice that was associated with neuroprotection of nigral and striatal neurons. The rescue of the phenotype correlated with the reduction of α-syn inclusions and oligomers in animals receiving ATH434. ATH434-treated mice exhibited significantly increased lysosomal activity of microglia without increased pro-inflammatory markers, suggesting a role in α-syn clearing. ATH434-treatment was associated with lower intracellular nigral iron levels.
CONCLUSIONS
Our findings demonstrate the beneficial disease-modifying effect of ATH434 in oligodendroglial α-synucleinopathy on both the motor phenotype and neurodegenerative pathology in the PLP-α-syn transgenic mouse and support the development of ATH434 for MSA. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Animals; Disease Models, Animal; Mice; Mice, Transgenic; Multiple System Atrophy; Oligodendroglia; alpha-Synuclein
PubMed: 34236731
DOI: 10.1002/mds.28714 -
Movement Disorders : Official Journal... Jul 2019
Topics: Humans; Multiple System Atrophy; Shy-Drager Syndrome
PubMed: 31322774
DOI: 10.1002/mds.27716 -
Brain Pathology (Zurich, Switzerland) May 2020Multiple system atrophy (MSA) and Parkinson's disease (PD) are synucleinopathies characterized by aggregation of α-synuclein in brain cells. Recent studies have shown...
Multiple system atrophy (MSA) and Parkinson's disease (PD) are synucleinopathies characterized by aggregation of α-synuclein in brain cells. Recent studies have shown that morphological changes in terms of cerebral nerve cell loss and increase in glia cell numbers, the degree of brain atrophy and molecular and epidemiological findings are more severe in MSA than PD. In the present study, we performed a stereological comparison of cerebellar volumes, granule and Purkinje cells in 13 patients diagnosed with MSA [8 MSA-P (striatonigral subtype) and 5 MSA-C (olivopontocerebellar subtype)], 12 PD patients, and 15 age-matched control subjects. Only brains from MSA-C patients showed a reduction in the total number of Purkinje cells (anterior lobe) whereas both MSA-P and MSA-C patients had reduced Purkinje cell volumes (perikaryons and nuclei volume). The cerebellum of both diseases showed a reduction in the white matter volume compared to controls. The number of granule cells was unaffected in both diseases. Analyses of cell type-specific mRNA expression supported our structural data. This study of the cerebellum is in line with previous findings in the cerebrum and demonstrates that the degree of morphological changes is more pronounced in MSA-C than MSA-P and PD. Further, our results support an explicit involvement of cerebellar Purkinje cells and white matter connectivity in MSA-C > MSA-P and points to the potential importance of white matter alterations in PD pathology.
Topics: Aged; Aged, 80 and over; Atrophy; Cerebellum; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Nerve Degeneration; Neurons; Organ Size; Parkinson Disease; Purkinje Cells; White Matter
PubMed: 31769073
DOI: 10.1111/bpa.12806 -
Brain : a Journal of Neurology Jun 2020Recent post-mortem studies reported 22-37% of patients with multiple system atrophy can develop cognitive impairment. With the aim of identifying associations between...
Recent post-mortem studies reported 22-37% of patients with multiple system atrophy can develop cognitive impairment. With the aim of identifying associations between cognitive impairment including memory impairment and α-synuclein pathology, 148 consecutive patients with pathologically proven multiple system atrophy were reviewed. Among them, 118 (79.7%) were reported to have had normal cognition in life, whereas the remaining 30 (20.3%) developed cognitive impairment. Twelve of them had pure frontal-subcortical dysfunction, defined as the presence of executive dysfunction, impaired processing speed, personality change, disinhibition or stereotypy; six had pure memory impairment; and 12 had both types of impairment. Semi-quantitative analysis of neuronal cytoplasmic inclusions in the hippocampus and parahippocampus revealed a disease duration-related increase in neuronal cytoplasmic inclusions in the dentate gyrus and cornu ammonis regions 1 and 2 of patients with normal cognition. In contrast, such a correlation with disease duration was not found in patients with cognitive impairment. Compared to the patients with normal cognition, patients with memory impairment (pure memory impairment: n = 6; memory impairment + frontal-subcortical dysfunction: n = 12) had more neuronal cytoplasmic inclusions in the dentate gyrus, cornu ammonis regions 1-4 and entorhinal cortex. In the multiple system atrophy mixed pathological subgroup, which equally affects the striatonigral and olivopontocerebellar systems, patients with the same combination of memory impairment developed more neuronal inclusions in the dentate gyrus, cornu ammonis regions 1, 2 and 4, and the subiculum compared to patients with normal cognition. Using patients with normal cognition (n = 18), frontal-subcortical dysfunction (n = 12) and memory impairment + frontal-subcortical dysfunction (n = 18), we further investigated whether neuronal or glial cytoplasmic inclusions in the prefrontal, temporal and cingulate cortices or the underlying white matter might affect cognitive impairment in patients with multiple system atrophy. We also examined topographic correlates of frontal-subcortical dysfunction with other clinical symptoms. Although no differences in neuronal or glial cytoplasmic inclusions were identified between the groups in the regions examined, frontal release signs were found more commonly when patients developed frontal-subcortical dysfunction, indicating the involvement of the frontal-subcortical circuit in the pathogenesis of frontal-subcortical dysfunction. Here, investigating cognitive impairment in the largest number of pathologically proven multiple system atrophy cases described to date, we provide evidence that neuronal cytoplasmic inclusion burden in the hippocampus and parahippocampus is associated with the occurrence of memory impairment in multiple system atrophy. Further investigation is necessary to identify the underlying pathological basis of frontal-subcortical dysfunction in multiple system atrophy.
Topics: Adult; Aged; Bodily Secretions; Brain; Cognition; Cognitive Dysfunction; Dementia; Female; Hippocampus; Humans; Inclusion Bodies; Male; Memory; Memory Disorders; Middle Aged; Multiple System Atrophy; Neurons; alpha-Synuclein
PubMed: 32385496
DOI: 10.1093/brain/awaa126 -
Biology Jun 2022Multiple-system atrophy (MSA) is primarily an autonomic disorder with parkinsonism or cerebellar ataxia. Clinical diagnosis of MSA at an early stage is challenging...
Multiple-system atrophy (MSA) is primarily an autonomic disorder with parkinsonism or cerebellar ataxia. Clinical diagnosis of MSA at an early stage is challenging because the symptoms change over the course of the disease. Recently, various artificial intelligence-based programs have been developed to improve the diagnostic accuracy of neurodegenerative diseases, but most are limited to the evaluation of diagnostic imaging. In this study, we examined the validity of diagnosis of MSA using a pointwise linear model (deep learning-based method). The goal of the study was to identify features associated with disease differentiation that were found to be important in deep learning. A total of 3377 registered MSA cases from FY2004 to FY2008 were used to train the model. The diagnostic probabilities of SND (striatonigral degeneration), SDS (Shy-Drager syndrome), and OPCA (olivopontocerebellar atrophy) were estimated to be 0.852 ± 0.107, 0.650 ± 0.235, and 0.858 ± 0.270, respectively. In the pointwise linear model used to identify and visualize features involved in individual subtypes, autonomic dysfunction was found to be a more prominent component of SDS compared to SND and OPCA. Similarly, respiratory failure was identified as a characteristic of SDS, dysphagia was identified as a characteristic of SND, and brain-stem atrophy was identified as a characteristic of OPCA.
PubMed: 36101332
DOI: 10.3390/biology11070951 -
Physiotherapy Theory and Practice May 2023Amplitude-based exercise training has been shown to be effective in the motor performance of individuals with idiopathic Parkinson's disease, with limited research...
BACKGROUND
Amplitude-based exercise training has been shown to be effective in the motor performance of individuals with idiopathic Parkinson's disease, with limited research investigating its effects on Parkinson plus syndromes such as olivopontocerebellar atrophy (OPCA). The purpose of this clinical case report is to examine the effects of amplitude-based training exercises on an individual with OPCA.
CASE DESCRIPTION
A 68-year-old man with a 14-month history of OPCA presented to physical therapy with bradykinesia, rigidity, and postural instability. The individual participated in 34 intervention sessions. Pre- and post-test measurements were collected for the following outcome measures: Five Times Sit to Stand (FTSTS); Functional Gait Assessment (FGA); Activities-Specific Balance Confidence Scale (ABC-6); 9 Hole Peg Test (9HPT); preferred and maximal gait speed.
OUTCOMES
Improvements reaching Minimum Detectable Change (MDC) or Minimal Clinically Important Difference (MCID) were recorded with a pre (Week 1) and post (Week 20) intervention: FGA score (4-point improvement (MDC = 4 points), preferred gait speed (0.09 meters/second improvement (MCID = 0.05 meters/second)), FTSTS (6-second improvement (MDC = 2.3 seconds)), and 9HPT on the dominant hand (3-second improvement (MDC = 2.6 seconds)). Fluctuations during the plan of care were observed for these measures, and additional outcomes did not demonstrate a worsening of function.
CONCLUSION
In an individual with OPCA, amplitude-based exercise training as a component of the plan of care increased dynamic balance in walking, gait speed, and hand dexterity. However, these results need to be validated on a larger sample of individuals with OPCA through randomized controlled trials.
PubMed: 37165996
DOI: 10.1080/09593985.2023.2210218 -
BMC Medical Genomics Jun 2023Bi-allelic variants in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been involved in early-onset encephalopathies classified as pontocerebellar...
Bi-allelic variants in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been involved in early-onset encephalopathies classified as pontocerebellar hypoplasia (PCH) type 6 and in epileptic encephalopathy. A variant (NM_020320.3:c.-2A > G) in the promoter and 5'UTR of the RARS2 gene has been previously identified in a family with PCH. Only a mild impact of this variant on the mRNA level has been detected. As RARS2 is non-dosage-sensitive, this observation is not conclusive in regard of the pathogenicity of the variant.We report and describe here a new patient with the same variant in the RARS2 gene, at the homozygous state. This patient presents with a clinical phenotype consistent with PCH6 although in the absence of lactic acidosis. In agreement with the previous study, we measured RARS2 mRNA levels in patient's fibroblasts and detected a partially preserved gene expression compared to control. Importantly, this variant is located in the Kozak sequence that controls translation initiation. Therefore, we investigated the impact on protein translation using a bioinformatic approach and western blotting. We show here that this variant, additionally to its effect on the transcription, also disrupts the consensus Kozak sequence, and has a major impact on RARS2 protein translation. Through the identification of this additional case and the characterization of the molecular consequences, we clarified the involvement of this Kozak variant in PCH and on protein synthesis. This work also points to the current limitation in the pathogenicity prediction of variants located in the translation initiation region.
Topics: Humans; Cerebellar Diseases; Olivopontocerebellar Atrophies; RNA, Messenger; Arginine-tRNA Ligase
PubMed: 37344844
DOI: 10.1186/s12920-023-01582-z