scholarly journals Phosphorylated NUB1 distinguishes α‐synuclein in Lewy bodies from that in glial cytoplasmic inclusions in multiple system atrophy

2019 ◽  
Vol 29 (6) ◽  
pp. 803-812 ◽  
Author(s):  
Kunikazu Tanji ◽  
Yasuo Miki ◽  
Fumiaki Mori ◽  
Tomoya Kon ◽  
Akiyoshi Kakita ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Lewy Bodies ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions

scholarly journals Autophagy in α-Synucleinopathies—An Overstrained System

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3143
Author(s):  
Lisa Fellner ◽  
Elisa Gabassi ◽  
Johannes Haybaeck ◽  
Frank Edenhofer
Keyword(s):  
Multiple System Atrophy ◽  
Dementia With Lewy Bodies ◽  
Trigger Point ◽  
Lewy Bodies ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Inclusion Formation ◽  
Intracytoplasmic Inclusion ◽  
Current Review ◽  
Disease Initiation

Alpha-synucleinopathies comprise progressive neurodegenerative diseases, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). They all exhibit the same pathological hallmark, which is the formation of α-synuclein positive deposits in neuronal or glial cells. The aggregation of α-synuclein in the cell body of neurons, giving rise to the so-called Lewy bodies (LBs), is the major characteristic for PD and DLB, whereas the accumulation of α-synuclein in oligodendroglial cells, so-called glial cytoplasmic inclusions (GCIs), is the hallmark for MSA. The mechanisms involved in the intracytoplasmic inclusion formation in neuronal and oligodendroglial cells are not fully understood to date. A possible mechanism could be an impaired autophagic machinery that cannot cope with the high intracellular amount of α-synuclein. In fact, different studies showed that reduced autophagy is involved in α-synuclein aggregation. Furthermore, altered levels of different autophagy markers were reported in PD, DLB, and MSA brains. To date, the trigger point in disease initiation is not entirely clear; that is, whether autophagy dysfunction alone suffices to increase α-synuclein or whether α-synuclein is the pathogenic driver. In the current review, we discuss the involvement of defective autophagy machinery in the formation of α-synuclein aggregates, propagation of α-synuclein, and the resulting neurodegenerative processes in α-synucleinopathies.

scholarly journals Luminescent conjugated oligothiophenes distinguish between α-synuclein assemblies of Parkinson’s disease and multiple system atrophy

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Therése Klingstedt ◽  
Bernardino Ghetti ◽  
Janice L. Holton ◽  
Helen Ling ◽  
K. Peter R. Nilsson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Lewy Bodies ◽  
Fluorescence Lifetime Imaging ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Lewy Pathology ◽  
Lifetime Imaging ◽  
The Difference

AbstractSynucleinopathies [Parkinson’s disease with or without dementia, dementia with Lewy bodies and multiple system atrophy] are neurodegenerative diseases that are defined by the presence of filamentous α-synuclein inclusions. We investigated the ability of luminescent conjugated oligothiophenes to stain the inclusions of Parkinson’s disease and multiple system atrophy. They stained the Lewy pathology of Parkinson’s disease and the glial cytoplasmic inclusions of multiple system atrophy. Spectral analysis of HS-68-stained inclusions showed a red shift in multiple system atrophy, but the difference with Parkinson’s disease was not significant. However, when inclusions were double-labelled for HS-68 and an antibody specific for α-synuclein phosphorylated at S129, they could be distinguished based on colour shifts with blue designated for Parkinson’s disease and red for multiple system atrophy. The inclusions of Parkinson’s disease and multiple system atrophy could also be distinguished using fluorescence lifetime imaging. These findings are consistent with the presence of distinct conformers of assembled α-synuclein in Parkinson’s disease and multiple system atrophy.

scholarly journals Neurons and Glia Interplay in α-Synucleinopathies

2021 ◽  
Vol 22 (9) ◽  
pp. 4994
Author(s):  
Panagiota Mavroeidi ◽  
Maria Xilouri
Keyword(s):  
Glial Cells ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Lewy Neurites ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Glial Function ◽  
Presynaptic Protein

Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

Subthalamic nucleus deep brain stimulation in a patient with levodopa-responsive multiple system atrophy

2004 ◽  
Vol 100 (3) ◽  
pp. 553-556 ◽  
Author(s):  
Kelvin L. Chou ◽  
Mark S. Forman ◽  
John Q. Trojanowski ◽  
Howard I. Hurtig ◽  
Gordon H. Baltuch
Keyword(s):  
Deep Brain Stimulation ◽  
Multiple System Atrophy ◽  
Subthalamic Nucleus ◽  
Brain Stimulation ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Content Type ◽  
Clinicopathological Findings ◽  
Diagnostic Modalities ◽  
Deep Brain

✓ The authors report the clinicopathological findings in a patient in whom levodopa-responsive parkinsonism developed at 45 years of age. The patient experienced asymmetrical onset of symptoms, sustained benefit from levodopa, and motor fluctuations and dyskinesias, but there were no prominent autonomic, cerebellar, or pyramidal signs. He was diagnosed clinically with Parkinson disease (PD) and underwent bilateral subthalamic nucleus deep brain stimulation (DBS) surgery 9 years after symptom onset. He did not respond to stimulation or medication postoperatively, however, and died 12 weeks after surgery of repeated aspiration pneumonias. Postmortem examination revealed neuron loss in the substantia nigra and basal ganglia, and numerous α-synuclein—positive glial cytoplasmic inclusions in the subcortical nuclei, cerebellum, and brainstem, findings that established a neuropathological diagnosis of multiple system atrophy (MSA). Furthermore, there was an atypical and robust inflammatory reaction, as well as numerous glial cytoplasmic inclusions surrounding both DBS electrode termination sites. The authors speculate that the presence of α-synuclein in the striatum, combined with the inflammation surrounding the electrodes, contributed to the ineffectiveness of stimulation and dopaminergic medications postoperatively. This case demonstrates the ineffectiveness of DBS in MSA, even when the patient is responsive to levodopa, and emphasizes the need for diagnostic modalities that can be used to distinguish PD from MSA and other parkinsonian syndromes in which the levodopa response pattern is typical of PD.

scholarly journals Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Ethan W. Hass ◽  
Zachary A. Sorrentino ◽  
Grace M. Lloyd ◽  
Nikolaus R. McFarland ◽  
Stefan Prokop ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Lewy Bodies ◽  
Biochemical Properties ◽  
Detection Methods ◽  
Inferior Olivary Nucleus ◽  
Cytoplasmic Inclusions ◽  
Neuronal Populations ◽  
Carboxy Terminal Region ◽  
High Level ◽  
Carboxy Terminal

AbstractMultiple system atrophy (MSA) is an insidious middle age-onset neurodegenerative disease that clinically presents with variable degrees of parkinsonism and cerebellar ataxia. The pathological hallmark of MSA is the progressive accumulation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes that are comprised of α-synuclein (αSyn) aberrantly polymerized into fibrils. Experimentally, MSA brain samples display a high level of seeding activity to induce further αSyn aggregation by a prion-like conformational mechanism. Paradoxically, αSyn is predominantly a neuronal brain protein, with only marginal levels expressed in normal or diseased oligodendrocytes, and αSyn inclusions in other neurodegenerative diseases, including Parkinson’s disease and Dementia with Lewy bodies, are primarily found in neurons. Although GCIs are the hallmark of MSA, using a series of new monoclonal antibodies targeting the carboxy-terminal region of αSyn, we demonstrate that neuronal αSyn pathology in MSA patient brains is remarkably abundant in the pontine nuclei and medullary inferior olivary nucleus. This neuronal αSyn pathology has distinct histological properties compared to GCIs, which allows it to remain concealed to many routine detection methods associated with altered biochemical properties of the carboxy-terminal domain of αSyn. We propose that these previously underappreciated sources of aberrant αSyn could serve as a pool of αSyn prion seeds that can initiate and continue to drive the pathogenesis of MSA.

P39 immunoreactivity in glial cytoplasmic inclusions in brains with multiple system atrophy

2001 ◽  
Vol 101 (3) ◽  
pp. 190-194 ◽  
Author(s):  
Yasuyuki Honjyo ◽  
Yasuhiro Kawamoto ◽  
Shinichi Nakamura ◽  
Satoshi Nakano ◽  
Ichiro Akiguchi
Keyword(s):  
Multiple System Atrophy ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions

Reversible conformational change of tau2 epitope on exposure to detergent in glial cytoplasmic inclusions of multiple system atrophy

2003 ◽  
Vol 105 (5) ◽  
pp. 508-514 ◽  
Author(s):  
Katsuhiko Shibuya ◽  
Toshiki Uchihara ◽  
Ayako Nakamura ◽  
Miyako Ishiyama ◽  
Keiko Yamaoka ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Conformational Change ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions

scholarly journals Models of multiple system atrophy

2019 ◽  
Vol 51 (11) ◽  
pp. 1-10 ◽  
Author(s):  
He-Jin Lee ◽  
Diadem Ricarte ◽  
Darlene Ortiz ◽  
Seung-Jae Lee
Keyword(s):  
Animal Models ◽  
Multiple System Atrophy ◽  
Mouse Models ◽  
Clinical Manifestations ◽  
Lewy Bodies ◽  
Model Systems ◽  
Future Research ◽  
Cytoplasmic Inclusions ◽  
Cellular Models ◽  
Brain Extracts

AbstractMultiple system atrophy (MSA) is a neurodegenerative disease with diverse clinical manifestations, including parkinsonism, cerebellar syndrome, and autonomic failure. Pathologically, MSA is characterized by glial cytoplasmic inclusions in oligodendrocytes, which contain fibrillary forms of α-synuclein. MSA is categorized as one of the α-synucleinopathy, and α-synuclein aggregation is thought to be the culprit of the disease pathogenesis. Studies on MSA pathogenesis are scarce relative to studies on the pathogenesis of other synucleinopathies, such as Parkinson’s disease and dementia with Lewy bodies. However, recent developments in cellular and animal models of MSA, especially α-synuclein transgenic models, have driven advancements in research on this disease. Here, we review the currently available models of MSA, which include toxicant-induced animal models, α-synuclein-overexpressing cellular models, and mouse models that express α-synuclein specifically in oligodendrocytes through cell type-specific promoters. We will also discuss the results of studies in recently developed transmission mouse models, into which MSA brain extracts were intracerebrally injected. By reviewing the findings obtained from these model systems, we will discuss what we have learned about the disease and describe the strengths and limitations of the models, thereby ultimately providing direction for the design of better models and future research.

scholarly journals Hippocampal α-synuclein pathology correlates with memory impairment in multiple system atrophy

Brain ◽  
2020 ◽  
Vol 143 (6) ◽  
pp. 1798-1810 ◽  
Author(s):  
Yasuo Miki ◽  
Sandrine C Foti ◽  
Daniela Hansen ◽  
Kate M Strand ◽  
Yasmine T Asi ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Multiple System Atrophy ◽  
Dentate Gyrus ◽  
Memory Impairment ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Cornu Ammonis ◽  
Neuronal Cytoplasmic Inclusions ◽  
With Memory ◽  
Normal Cognition

Abstract 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.

Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble ?-synuclein

1998 ◽  
Vol 44 (3) ◽  
pp. 415-422 ◽  
Author(s):  
Pang-hsien Tu ◽  
James E. Galvin ◽  
Minami Baba ◽  
Benoit Giasson ◽  
Taisuke Tomita ◽  
...  
Keyword(s):  
White Matter ◽  
Multiple System Atrophy ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions
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