Suppression of dynamin GTPase decreases α-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy

Molecular Neurodegeneration

Atsushi Takeda³  Yasuto Itoyama¹  Masashi Aoki³  Tsutomu Sasaki⁴  Fabienne C Fiesel²  Akio Kikuchi³  Naoto Sugeno³  Emiko Miura³  Toru Baba³  Takafumi Hasegawa³  Masatoshi Konno³ 

[1] National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, 187-8502, Japan;Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA;Division of Neurology, Department of Neuroscience and Sensory Organs, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8574, Japan;Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan

关键词: Multiple system atrophy;    Parkinson’s disease;    Sertraline;    Dynamin;    Endocytosis;    Inclusions;    Transmission;    Oligodendroglia;    Neuron;    α-synuclein;   

Others  :  863783
DOI  :  10.1186/1750-1326-7-38

 received in 2012-03-05, accepted in 2012-08-06,  发布年份 2012

【 摘 要 】

Background

The intracellular deposition of misfolded proteins is a common neuropathological hallmark of most neurodegenerative disorders. Increasing evidence suggests that these pathogenic proteins may spread to neighboring cells and induce the propagation of neurodegeneration.

Results

In this study, we have demonstrated that α-synuclein (αSYN), a major constituent of intracellular inclusions in synucleinopathies, was taken up by neuronal and oligodendroglial cells in both a time- and concentration-dependent manner. Once incorporated, the extracellular αSYN was immediately assembled into high-molecular-weight oligomers and subsequently formed cytoplasmic inclusion bodies. Furthermore, αSYN uptake by neurons and cells of the oligodendroglial lineage was markedly decreased by the genetic suppression and pharmacological inhibition of the dynamin GTPases, suggesting the involvement of the endocytic pathway in this process.

Conclusions

Our findings shed light on the mode of αSYN uptake by neuronal and oligodendroglial cells and identify therapeutic strategies aimed at reducing the propagation of protein misfolding.

【 授权许可】

   
2012 Konno et al.; licensee BioMed Central Ltd.

【 图 表 】

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