The direct and indirect effects of &amp;alpha;-synuclein on microtubule stability in the pathogenesis of Parkinson&amp;rsquo;s disease

Carnwath, Tom; Mohammed, Raihan; Tsiang, Daniel

doi:10.2147/ndt.s166322

Cited by 39 publications

(41 citation statements)

References 41 publications

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“…37 The phosphorylation of Tau reduces its affinity for microtubules and accumulation in the brain and causing related Tauopathies, 17 and also impact on microtubule binding and induces microtubule instability. 4 Although p-Tau links to the pathogenesis of AD and other Tauopathies, recent studies have revealed that p-Tau has a relationship with PD. 46 MAPT (encoded Tau protein) gene mutation in humans increases the risk of PD, and Tau aggregation and filaments have been observed in familial PD.…”

Section: Introductionmentioning

confidence: 99%

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Hu¹,

Hu²,

Liu³

et al. 2020

NDT

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Parkinson's disease (PD) is the second most common neurodegenerative disease. The α-Synuclein is a major component of Lewy bodies and Lewy neurites, the pathologic hallmark of PD. It is known that α-Synuclein is phosphorylated (p-α-Synuclein) in PD and tau-hyperphosphorylation (p-Tau) is also a pathologic feature of PD. However, the relationship between p-Synuclein and p-Tau in PD is not clear, in particular in the MPTP model of PD. The purpose of this study was to reveal their relationship in the mouse MPTP model. Methods: Firstly, the p-α-Synuclein, α-Synuclein, p-Tau and Tau protein levels were analyzed. Then, GSK3β activation was determined using immunoblot and immunohistochemical staining. Finally, the dopaminergic neurodegeneration was assessed using Tyrosine Hydroxylase (TH) staining and retrograde labeling and microglial marker were labeled. Microglial activation and nigrostriatal pathway degeneration were observed. Results: The results showed that p-α-Synuclein, α-Synuclein, p-Tau and Tau were upregulated in both hippocampus and substantia nigra of the PD mouse model. Furthermore, p-α-Synuclein and p-Tau were localized in the same regions of substantial nigra (SN) and dentate gyrus (DG) of hippocampus (Hippo). The activated form of GSK3β (phosphor GSK3β Y216) was increased in multiple brain areas. The GSK3β inhibitor AZD1080 injected in MPTP mice suppressed the expression of p-Tau and p-GSK3β and improved motor functions. Conclusion: These findings revealed that p-α-Synuclein and p-Tau proteins are key pathological events leading to neurodegeneration and motor dysfunctions in the mouse MPTP model of PD. Our data suggest that the interference with the GSK3β activity may be an effective approach for the treatment of PD.

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Section: Introductionmentioning

confidence: 99%

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Hu¹,

Hu²,

Liu³

et al. 2020

NDT

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“…The current revision summarizes the studies supporting the link between αSyn and the actin cytoskeleton. This is an important topic as while the interplay between αSyn and the microtubules was recently reviewed (Carnwath et al, 2018;Calogero et al, 2019), the link αSyn-actin was less explored. Considering the αSyn structural features responsible for the interaction with cytoskeleton components, it was described that αSyn is a functional microtubule-associated protein with its C-terminal region suggested to be responsible for the interaction with microtubules (Alim et al, 2004;Cartelli et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Linking Alpha-Synuclein to the Actin Cytoskeleton: Consequences to Neuronal Function

Silva

Liz

2020

Front. Cell Dev. Biol.

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Alpha-Synuclein (αSyn), a protein highly enriched in neurons where it preferentially localizes at the pre-synapse, has been in the spotlight because its intraneuronal aggregation is a central phenomenon in Parkinson's disease. However, the consequences of αSyn accumulation to neuronal function are not fully understood. Considering the crucial role of actin on synaptic function and the fact that dysregulation of this cytoskeleton component is emerging in neurodegenerative disorders, the impact of αSyn on actin is a critical point to be addressed. In this review we explore the link between αSyn and actin and its significance for physiology and pathology. We discuss the relevance of αSyn-actin interaction for synaptic function and highlight the actindepolymerizing protein cofilin-1 as a key player on αSyn-induced actin dysfunction in Parkinson's disease.

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“…By directly or indirectly binding tubulin, these proteins have been reported to modulate MT stability and function [ 268 , 269 , 270 , 271 , 272 ].…”

Section: Microtubule Dysfunction and Neurodegenerationmentioning

confidence: 99%

“…α-Syn is a small, soluble unfolded protein that localizes predominantly to presynaptic terminals of neurons [ 286 ]. Although little is known about the mechanisms through which α-Syn acts in PD, different studies have recently proposed that this protein may act as a functional MAP by directly binding MTs [ 272 , 287 ] and regulating their stability. However, the effect of this interaction has been quite controversial, since different studies have reported that α-Syn, promotes MT stabilization, while others suggested the opposite effect [ 287 , 288 ].…”

Section: Microtubule Dysfunction and Neurodegenerationmentioning

confidence: 99%

Microtubule Dysfunction: A Common Feature of Neurodegenerative Diseases

Sferra

Nicita

Bertini

2020

IJMS

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Neurons are particularly susceptible to microtubule (MT) defects and deregulation of the MT cytoskeleton is considered to be a common insult during the pathogenesis of neurodegenerative disorders. Evidence that dysfunctions in the MT system have a direct role in neurodegeneration comes from findings that several forms of neurodegenerative diseases are associated with changes in genes encoding tubulins, the structural units of MTs, MT-associated proteins (MAPs), or additional factors such as MT modifying enzymes which modulating tubulin post-translational modifications (PTMs) regulate MT functions and dynamics. Efforts to use MT-targeting therapeutic agents for the treatment of neurodegenerative diseases are underway. Many of these agents have provided several benefits when tested on both in vitro and in vivo neurodegenerative model systems. Currently, the most frequently addressed therapeutic interventions include drugs that modulate MT stability or that target tubulin PTMs, such as tubulin acetylation. The purpose of this review is to provide an update on the relevance of MT dysfunctions to the process of neurodegeneration and briefly discuss advances in the use of MT-targeting drugs for the treatment of neurodegenerative disorders.

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The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease

Cited by 39 publications

References 41 publications

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Linking Alpha-Synuclein to the Actin Cytoskeleton: Consequences to Neuronal Function

Microtubule Dysfunction: A Common Feature of Neurodegenerative Diseases

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