The AAA-ATPase VPS4 Regulates Extracellular Secretion and Lysosomal Targeting of [alpha]-Synuclein

• Published in: PloS one Vol. 6; no. 12; p. e29460
• Main Authors: Hasegawa, Takafumi, Konno, Masatoshi, Baba, Toru, Sugeno, Naoto, Kikuchi, Akio, Kobayashi, Michiko, Miura, Emiko, Tanaka, Nobuyuki, Tamai, Keiichi, Furukawa, Katsutoshi, Arai, Hiroyuki, Mori, Fumiaki, Wakabayashi, Koichi, Aoki, Masashi, Itoyama, Yasuto, Takeda, Atsushi
• Format: Journal Article
• Language: English
• Published: Public Library of Science 22.12.2011
• Subjects: ATPases; Nervous system diseases; Neurons; Prions (Proteins)
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0029460

Many neurodegenerative diseases share a common pathological feature: the deposition of amyloid-like fibrils composed of misfolded proteins. Emerging evidence suggests that these proteins may spread from cell-to-cell and encourage the propagation of neurodegeneration in a prion-like manner. Here, we demonstrated that [alpha]-synuclein ([alpha]SYN), a principal culprit for Lewy pathology in Parkinson's disease (PD), was present in endosomal compartments and detectably secreted into the extracellular milieu. Unlike prion protein, extracellular [alpha]SYN was mainly recovered in the supernatant fraction rather than in exosome-containing pellets from the neuronal culture medium and cerebrospinal fluid. Surprisingly, impaired biogenesis of multivesicular body (MVB), an organelle from which exosomes are derived, by dominant-negative mutant vacuolar protein sorting 4 (VPS4) not only interfered with lysosomal targeting of [alpha]SYN but facilitated [alpha]SYN secretion. The hypersecretion of [alpha]SYN in VPS4-defective cells was efficiently restored by the functional disruption of recycling endosome regulator Rab11a. Furthermore, both brainstem and cortical Lewy bodies in PD were found to be immunoreactive for VPS4. Thus, VPS4, a master regulator of MVB sorting, may serve as a determinant of lysosomal targeting or extracellular secretion of [alpha]SYN and thereby contribute to the intercellular propagation of Lewy pathology in PD.