Rab11a and HSP90 regulate recycling of extracellular alpha-synuclein.
Growing evidence suggests that extracellular alpha-synuclein (eSNCA) may play an important role in the pathogenesis of Parkinson's disease (PD) and related synucleinopathies by producing neurotoxicity directly or via activation of glia. However, the mechanisms involved in the trafficking of eSNCA in neurons and/or glia remain unclear. Here, we demonstrated that eSNCA could be resecreted out of neurons via a process modulated by a recycling endosome regulator rab11a in addition to being degraded by an endosome-lysosome system. A quantitative proteomic analysis also revealed numerous proteins through which rab11a might execute its function. One of the candidate proteins, heat shock protein 90 (HSP90), was validated to be interacting with rab11a. Furthermore, geldanamycin, an HSP90 inhibitor, not only prevented resecretion of eSNCA but also attenuated neurotoxicity induced by eSNCA.
Liu
Jun
J
Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
Zhang
Jian-Peng
JP
Shi
Min
M
Quinn
Thomas
T
Bradner
Joshua
J
Beyer
Richard
R
Chen
Shengdi
S
Zhang
Jing
J
D002478:Cells, Cultured; D005089:Exocytosis / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism* / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D009474:Neurons / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051844:alpha-Synuclein / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000502:physiology*; D000099193:rab11 GTP-Binding Proteins
D018841:HSP90 Heat-Shock Proteins; D051844:alpha-Synuclein; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins