Autophagy in α-Synucleinopathies—An Overstrained System

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.

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

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0840-1 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 11

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.

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Autophagy in Synucleinopathy: The Overwhelmed and Defective Machinery

Cells ◽

10.3390/cells8060565 ◽

2019 ◽

Vol 8 (6) ◽

pp. 565 ◽

Cited By ~ 17

Author(s):

Marie-Laure Arotcarena ◽

Margaux Teil ◽

Benjamin Dehay

Keyword(s):

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Therapeutic Approaches ◽

Cytoplasmic Inclusions ◽

Glial Cytoplasmic Inclusions ◽

Intracytoplasmic Inclusions ◽

Potential Link ◽

The Common ◽

Protein Toxicity

Alpha-synuclein positive-intracytoplasmic inclusions are the common denominators of the synucleinopathies present as Lewy bodies in Parkinson’s disease, dementia with Lewy bodies, or glial cytoplasmic inclusions in multiple system atrophy. These neurodegenerative diseases also exhibit cellular dyshomeostasis, such as autophagy impairment. Several decades of research have questioned the potential link between the autophagy machinery and alpha-synuclein protein toxicity in synucleinopathy and neurodegenerative processes. Here, we aimed to discuss the active participation of autophagy impairment in alpha-synuclein accumulation and propagation, as well as alpha-synuclein-independent neurodegenerative processes in the field of synucleinopathy. Therapeutic approaches targeting the restoration of autophagy have started to emerge as relevant strategies to reverse pathological features in synucleinopathies.

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

Brain Pathology ◽

10.1111/bpa.12728 ◽

2019 ◽

Vol 29 (6) ◽

pp. 803-812 ◽

Cited By ~ 2

Author(s):

Kunikazu Tanji ◽

Yasuo Miki ◽

Fumiaki Mori ◽

Tomoya Kon ◽

Akiyoshi Kakita ◽

...

Keyword(s):

Multiple System Atrophy ◽

Lewy Bodies ◽

Cytoplasmic Inclusions ◽

Glial Cytoplasmic Inclusions

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Neurons and Glia Interplay in α-Synucleinopathies

International Journal of Molecular Sciences ◽

10.3390/ijms22094994 ◽

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.

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

Journal of Neurosurgery ◽

10.3171/jns.2004.100.3.0553 ◽

2004 ◽

Vol 100 (3) ◽

pp. 553-556 ◽

Cited By ~ 42

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.

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

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01173-y ◽

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.

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Is pure autonomic failure an early marker for Parkinson disease, dementia with Lewy bodies, and multiple system atrophy? And other updates on recent autonomic research

Clinical Autonomic Research ◽

10.1007/s10286-017-0408-8 ◽

2017 ◽

Vol 27 (2) ◽

pp. 71-73 ◽

Cited By ~ 8

Author(s):

Srikanth Muppidi ◽

Mitchell G. Miglis

Keyword(s):

Multiple System Atrophy ◽

Parkinson Disease ◽

Dementia With Lewy Bodies ◽

Autonomic Failure ◽

Lewy Bodies ◽

Pure Autonomic Failure ◽

Autonomic Research ◽

Early Marker

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Structures of α-synuclein filaments from multiple system atrophy

10.1101/2020.02.05.935619 ◽

2020 ◽

Cited By ~ 6

Author(s):

Manuel Schweighauser ◽

Yang Shi ◽

Airi Tarutani ◽

Fuyuki Kametani ◽

Alexey G. Murzin ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Human Brain ◽

Multiple System Atrophy ◽

Recombinant Proteins ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Two Dimensional ◽

Filamentous Inclusions

Synucleinopathies are human neurodegenerative diseases that include multiple system atrophy (MSA), Parkinson’s disease, Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) (1). Existing treatments are at best symptomatic. These diseases are characterised by the presence in brain cells of filamentous inclusions of α-synuclein, the formation of which is believed to cause disease (2, 3). However, the structures of α-synuclein filaments from human brain are not known. Here we show, using electron cryo-microscopy, that α-synuclein inclusions from MSA are made of two types of filaments, each of which consists of two different protofilaments. Non-proteinaceous molecules are present at the protofilament interfaces. By two-dimensional class averaging, we show that α-synuclein filaments from the brains of patients with MSA and DLB are different, suggesting that distinct conformers (or strains) characterise synucleinopathies. As was the case of tau assemblies (4–9), the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, with implications for understanding the mechanisms of aggregate propagation and neurodegeneration in human brain. These findings have diagnostic and potential therapeutic relevance, especially in view of the unmet clinical need to be able to image filamentous α-synuclein inclusions in human brain.

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