Rab11a and HSP90 Regulate Recycling of Extracellular α-Synuclein

Abstract

Growing evidence suggests that extracellular α-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 re-secreted 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 re-secretion of eSNCA but also attenuated neurotoxicity induced by eSNCA.

α-Synuclein Membrane Association Is Regulated by the Rab3a Recycling Machinery and Presynaptic Activity*

“…Several studies have linked ␣-syn with various Rab proteins, including interaction of ␣-syn and Rab3a in disease tissue (40 -42), disruption of endoplasmic reticulumGolgi trafficking by ␣-syn rescued by Rab1 or Rab3a (43,44), and uptake and secretion of extracellular ␣-syn involving Rab1A and Hsp90 (45). However, the ␣-syn and Rab3a relationship in healthy neurons is not understood.…”

The Molecular Chaperone Hsp90 Modulates Intermediate Steps of Amyloid Assembly of the Parkinson-related Protein α-Synuclein

“…Hsp90 was further found to suppress AS toxicity in yeast genetic screenings (20). Finally, Hsp90 was shown to regulate rab11a-dependent secretion and recycling of AS (21).…”

“…The remaining residues (106 -140) were not significantly affected. The most affected residues formed a pattern located around two basic residues on amphipatic repeats (AAXKTK) on the N-terminal domain (Lys 21 and Lys 32 ), a T/G-rich region in the NAC region (Thr 64 , Gly 67 , Thr 75 , Thr 81 , and Gly 85 ), and two acidic residues in the upper C-terminal domain (Asp 98 and Asn 103 ). These findings suggest multiple contacts between AS and Hsp90 rather than a localized interaction occurring.…”

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

“…Rab GTPases are small guanine nucleotide binding proteins that play a key role in coordinating vesicle trafficking (Stenmark, 2009), and have been associated with αS-related neuronal dysfunction (Chen et al, 2013;Chung et al, 2009;Dalfo et al, 2004a,b;Kuwahara et al, 2008;Liu et al, 2009;Sancenon et al, 2012;Soper et al, 2011). In cellular and animal models of PD, αS overexpression disrupts vesicle trafficking between the endoplasmic reticulum (ER) and Golgi and overexpression of Rab1 attenuated αS toxicity (Cooper et al, 2006).…”