The AAA-ATPase VPS4 regulates extracellular secretion and lysosomal targeting of α-synuclein

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...

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Bibliographic Details
Published in:PloS one 2011-12, Vol.6 (12), p.e29460-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: Article
Language:English
Subjects:
Adenosine triphosphatase
alpha-Synuclein - metabolism
Alzheimer's disease
Amino acids
Amyloid
Apoptosis
ATPases Associated with Diverse Cellular Activities
Biochemistry
Biology
Brain research
Brain stem
Cancer
Cell Compartmentation
Cell culture
Cerebrospinal fluid
Compartments
Cortex
Culture Media
Disruption
Dopamine
Endosomal Sorting Complexes Required for Transport - physiology
Endosomes - metabolism
Exosomes
Fibrils
Geriatrics
Gerontology
Humans
Kinases
Lewy bodies
Lysosomes - metabolism
Medicine
Metabolites
Movement disorders
Mutation
Neuroblastoma
Neurodegeneration
Neurodegenerative diseases
Neurological diseases
Neurology
Neuropathology
Neurosciences
Neurotoxicity
Parkinson's disease
Pathology
Physics
Prion protein
Propagation
Protein folding
Protein transport
Protein turnover
Proteins
Synuclein
University graduates
Vacuolar Proton-Translocating ATPases - physiology
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Summary: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 α-synuclein (αSYN), 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 αSYN 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 αSYN but facilitated αSYN secretion. The hypersecretion of αSYN 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 αSYN and thereby contribute to the intercellular propagation of Lewy pathology in PD.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0029460