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 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.
Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. thasegawa@med.tohoku.ac.jp
Takafumi
T
Hasegawa
Masatoshi
M
Konno
Toru
T
Baba
Naoto
N
Sugeno
Akio
A
Kikuchi
Michiko
M
Kobayashi
Emiko
E
Miura
Nobuyuki
N
Tanaka
Keiichi
K
Tamai
Katsutoshi
K
Furukawa
Hiroyuki
H
Arai
Fumiaki
F
Mori
Koichi
K
Wakabayashi
Masashi
M
Aoki
Yasuto
Y
Itoyama
Atsushi
A
Takeda
D000074183:ATPases Associated with Diverse Cellular Activities; D002451:Cell Compartmentation; D003470:Culture Media; D056827:Endosomal Sorting Complexes Required for Transport / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000502:physiology*; D051844:alpha-Synuclein / Q000378:metabolism*
D003470:Culture Media; D056827:Endosomal Sorting Complexes Required for Transport; D051844:alpha-Synuclein; D025262:Vacuolar Proton-Translocating ATPases; D000074183:ATPases Associated with Diverse Cellular Activities; C490305:VPS4A protein, human