Alpha-synuclein facilitates to form short unconventional microtubules that have a unique function in the axonal transport

Toba, Shiori; Jin, Mingyue; Yamada, Masami; Kumamoto, Kenzo; Matsumoto, Sakiko; Yasunaga, Takuo; Fukunaga, Yuko; Miyazawa, Atsuo; Fujita, Sakiko; Itoh, Kyoko; Fushiki, Shinji; Kojima, Hiroaki; Wanibuchi, Hideki; Arai, Yoshiyuki; Hirotsune, Shinji

doi:10.1038/s41598-017-15575-3

Cited by 29 publications

(32 citation statements)

References 61 publications

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“…αSyn interacts with α and β subunits of tubulin-promoting microtubules polymerization and enhancing the growth rate of axons [ 124 ]. αSyn co-localizes with dynein, which promotes retrograde transport and is a large motor complex composed of multiple subunits that require activation by dynactin; dynein dependent axonal transport is severely impaired without αSyn [ 125 ]. αSyn also plays a role for anterograde transport binding kinesin family member 5A (KIF5A), microtubule-associated protein 2 (MAP2), and tau [ 126 ].…”

Section: The Role Of Alpha Synuclein In Physiological Condition Inmentioning

confidence: 99%

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

Vacchi

Kaelin‐Lang

Melli

2020

IJMS

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In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer’s and Parkinson’s diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a “dying back” pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson’s disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies.

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Section: The Role Of Alpha Synuclein In Physiological Condition Inmentioning

confidence: 99%

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

Vacchi

Kaelin‐Lang

Melli

2020

IJMS

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“…Proteins that govern neuronal trafficking, like kinesin and dynein, which are implicated in the anterograde and the retrograde transport, have been shown to be altered in PD models with a strong association with motor deficits [158]. Dynein co-localizes with α-syn and dynein-dependent axonal transport is severely affected in the absence of α-syn [159] (Figure 2A). In physiological conditions, co-immunoprecipitation experiments confirmed a direct interaction of α-syn with the α and β subunits of tubulin that can promote the polymerization of microtubules.…”

Section: Alpha-synuclein Modulation Of Protein Trafficking At the mentioning

confidence: 99%

Living in Promiscuity: The Multiple Partners of Alpha-Synuclein at the Synapse in Physiology and Pathology

Longhena

Faustini

Spillantini

et al. 2019

IJMS

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Alpha-synuclein (α-syn) is a small protein that, in neurons, localizes predominantly to presynaptic terminals. Due to elevated conformational plasticity, which can be affected by environmental factors, in addition to undergoing disorder-to-order transition upon interaction with different interactants, α-syn is counted among the intrinsically disordered proteins (IDPs) family. As with many other IDPs, α-syn is considered a hub protein. This function is particularly relevant at synaptic sites, where α-syn is abundant and interacts with many partners, such as monoamine transporters, cytoskeletal components, lipid membranes, chaperones and synaptic vesicles (SV)-associated proteins. These protein–protein and protein–lipid membrane interactions are crucial for synaptic functional homeostasis, and alterations in α-syn can cause disruption of this complex network, and thus a failure of the synaptic machinery. Alterations of the synaptic environment or post-translational modification of α-syn can induce its misfolding, resulting in the formation of oligomers or fibrillary aggregates. These α-syn species are thought to play a pathological role in neurodegenerative disorders with α-syn deposits such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are referred to as synucleinopathies. Here, we aim at revising the complex and promiscuous role of α-syn at synaptic terminals in order to decipher whether α-syn molecular interactants may influence its conformational state, contributing to its aggregation, or whether they are just affected by it.

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“…Although not being a classic MT-associated protein, experimental evidence indicates that the presynaptic protein α-synuclein also interacts with MTs (Cartelli et al, 2016;Toba et al, 2017). Therefore, we decided to include α-synuclein (encoded by the SNCA gene) in our analysis, as it is known to be an IDP (Uversky, 2015).…”

Section: Intrinsically Disordered Regions -Mt-binding and Tubulin-seqmentioning

confidence: 99%

The microtubule skeleton and the evolution of neuronal complexity in vertebrates

Trushina

Mulkidjanian

Brandt

2019

Biological Chemistry

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The evolution of a highly developed nervous system is mirrored by the ability of individual neurons to develop increased morphological complexity. As microtubules (MTs) are crucially involved in neuronal development, we tested the hypothesis that the evolution of complexity is driven by an increasing capacity of the MT system for regulated molecular interactions as it may be implemented by a higher number of molecular players and a greater ability of the individual molecules to interact. We performed bioinformatics analysis on different classes of components of the vertebrate neuronal MT cytoskeleton. We show that the number of orthologs of tubulin structure proteins, MT-binding proteins and tubulin-sequestering proteins expanded during vertebrate evolution. We observed that protein diversity of MT-binding and tubulin-sequestering proteins increased by alternative splicing. In addition, we found that regions of the MT-binding protein tau and MAP6 displayed a clear increase in disorder extent during evolution. The data provide evidence that vertebrate evolution is paralleled by gene expansions, changes in alternative splicing and evolution of coding sequences of components of the MT system. The results suggest that in particular evolutionary changes in tubulin-structure proteins, MT-binding proteins and tubulin-sequestering proteins were prominent drivers for the development of increased neuronal complexity.

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Alpha-synuclein facilitates to form short unconventional microtubules that have a unique function in the axonal transport

Cited by 29 publications

References 61 publications

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

Living in Promiscuity: The Multiple Partners of Alpha-Synuclein at the Synapse in Physiology and Pathology

The microtubule skeleton and the evolution of neuronal complexity in vertebrates

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