Oligomeric α-synuclein inhibits tubulin polymerization

Chen, Leo; Jin, Jinghua; Davis, Jack; Zhou, Yong; Wang, Yan; Li, Jun; Lockhart, Paul J.; Zhang, Jing

doi:10.1016/j.bbrc.2007.02.163

Cited by 90 publications

(81 citation statements)

References 26 publications

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“…These data are in line with previous reports showing that ␣-Syn oligomers, when applied extracellularly, caused significant disruption of tubulin polymerization in a dopaminergic cell line (MES23.5), whereas no direct effect of ␣-Syn oligomers on MT assembly in vitro was seen in this study (23). Furthermore, overexpression of E57K led to more pronounced neurite degeneration and changes of neuronal network morphology than WTS.…”

Section: Discussionsupporting

confidence: 82%

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α-Synuclein Oligomers Impair Neuronal Microtubule-Kinesin Interplay

Prots

Veber

Brey

et al. 2013

Journal of Biological Chemistry

124

127

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Background: ␣-Synuclein aggregates cause early neurite pathology by as yet unknown mechanisms. Results: ␣-Synuclein oligomers and seeds decrease microtubule stability, kinesin-microtubule interaction, cellular cargo distribution, and neurite network morphology. Conclusion: Various ␣-synuclein species interact differently with proteins of axonal transport. Significance: The impairment of the microtubule-kinesin function by ␣-synuclein oligomers drives early neurite pathology.

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Section: Discussionsupporting

confidence: 82%

“…Together, these data strongly suggest alterations in the intracellular transport machinery in synucleinopathies. Although ␣-Syn oligomers were implicated in decreased tubulin polymerization in a cellular model (23), the specific relation of oligomers/fibrils and different compartments of the neuronal cytoskeletal machinery has not yet been elucidated.…”

mentioning

confidence: 99%

α-Synuclein Oligomers Impair Neuronal Microtubule-Kinesin Interplay

Prots

Veber

Brey

et al. 2013

Journal of Biological Chemistry

124

127

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“…Impaired retrograde transport can prevent maturation of autophagosomes, which can be further impaired by high levels of synaptic -synuclein (7). Specifically, oligomeric α-synuclein can inhibit tubulin polymerization disrupting proper axonal transport (7). Therefore, impaired transport mechanisms in the distal axon may lead to dystrophic neurites and accumulation of protein inclusions.…”

Section: Antioxidants and Redox Signalingmentioning

confidence: 99%

Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice

Rocha

Smith

Park

et al. 2015

Antioxidants & Redox Signaling

121

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Aims: Loss-of-function mutations in GBA1, which cause the autosomal recessive lysosomal storage disease, Gaucher disease (GD), are also a key genetic risk factor for the α-synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase and reductions in this enzyme result in the accumulation of the glycolipid substrates glucosylceramide and glucosylsphingosine. Deficits in autophagy and lysosomal degradation pathways likely contribute to the pathological accumulation of α-synuclein in PD. In this report we used conduritol-β-epoxide (CBE), a potent selective irreversible competitive inhibitor of glucocerebrosidase, to model reduced glucocerebrosidase activity in vivo, and tested whether sustained glucocerebrosidase inhibition in mice could induce neuropathological abnormalities including α-synucleinopathy, and neurodegeneration. Results: Our data demonstrate that daily systemic CBE treatment over 28 days caused accumulation of insoluble α-synuclein aggregates in the substantia nigra, and altered levels of proteins involved in the autophagy lysosomal system. These neuropathological changes were paralleled by widespread neuroinflammation, upregulation of complement C1q, abnormalities in synaptic, axonal transport and cytoskeletal proteins, and neurodegeneration. Innovation: A reduction in brain GCase activity has been linked to sporadic PD and normal aging, and may contribute to the susceptibility of vulnerable neurons to degeneration. This report demonstrates that systemic reduction of GCase activity using chemical inhibition, leads to neuropathological changes in the brain reminiscent of α-synucleinopathy. Conclusions: These data reveal a link between reduced glucocerebrosidase and the development of α-synucleinopathy and pathophysiological abnormalities in mice, and support the development of GCase therapeutics to reduce α-synucleinopathy in PD and related disorders. Antioxid. Redox Signal. 23, 550–564.

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“…There is some direct evidence that supports that S oligomers are likely to be toxic species. Upon extracellular addition to cultured cells, oligomeric S is more toxic than the monomeric and fibrillar forms of the protein [87][88][89][90][91][92]. Toxicity is reduced upon addition of an oligomer specific antibody [85,93].…”

Section: S Toxicitymentioning

confidence: 99%

Membrane Interactions of Oligomeric Alpha-Synuclein: Potential Role in Parkinsons Disease

Rooijen

Claessens²,

Subramaniam³

2010

CPPS

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alpha-Synuclein is a small neuronal protein that has been implicated to play an important role in Parkinson's disease. Genetic mutations and multiplications in the alpha-synuclein gene can cause familial forms of the disease. In aggregated fibrillar form, alpha-synuclein is the main component of Lewy bodies, the intraneuronal inclusion bodies characteristic of Parkinson's disease. The loss of functional dopaminergic neurons in Parkinson's disease may be caused by a gain in toxic function of the protein. Elucidating if this gain of toxic function is related to the aggregation of alpha-synuclein may be vital in understanding Parkinson's disease. Although there are many ideas on how alpha-synuclein could be involved in the disease, this review will focus on the amyloid pore hypothesis. This hypothesis assumes that aggregation intermediates or oligomers are more likely to be toxic than monomeric or fibrillar forms of the protein. Oligomeric species are thought to exercise their toxicity through permeabilization of cellular membranes. Membrane pore formation by an oligomeric intermediate might play a role in other neurodegenerative disorders in which protein aggregation and amyloid formation play a role, such as Alzheimer's disease. We will discuss the role of this hypothesis in Parkinson's disease.

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Oligomeric α-synuclein inhibits tubulin polymerization

Cited by 90 publications

References 26 publications

α-Synuclein Oligomers Impair Neuronal Microtubule-Kinesin Interplay

α-Synuclein Oligomers Impair Neuronal Microtubule-Kinesin Interplay

Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice

Membrane Interactions of Oligomeric Alpha-Synuclein: Potential Role in Parkinsons Disease

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