PMID- 30842285
OWN - NLM
STAT- In-Data-Review
LR  - 20190329
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 116
IP  - 12
DP  - 2019 Mar 19
TI  - Parkinson's disease-linked D620N VPS35 knockin mice manifest tau neuropathology
      and dopaminergic neurodegeneration.
PG  - 5765-5774
LID - 10.1073/pnas.1814909116 [doi]
AB  - Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene represent a
      cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A
      single missense mutation, D620N, is considered pathogenic based upon its
      segregation with disease in multiple families with PD. At present, the
      mechanism(s) by which familial VPS35 mutations precipitate neurodegeneration in
      PD are poorly understood. Here, we employ a germline D620N VPS35 knockin (KI)
      mouse model of PD to formally establish the age-related pathogenic effects of the
      D620N mutation at physiological expression levels. Our data demonstrate that a
      heterozygous or homozygous D620N mutation is sufficient to reproduce key
      neuropathological hallmarks of PD as indicated by the progressive degeneration of
      nigrostriatal pathway dopaminergic neurons and widespread axonal pathology.
      Unexpectedly, endogenous D620N VPS35 expression induces robust tau-positive
      somatodendritic pathology throughout the brain as indicated by abnormal
      hyperphosphorylated and conformation-specific tau, which may represent an
      important and early feature of mutant VPS35-induced neurodegeneration in PD. In
      contrast, we find no evidence for alpha-synuclein-positive neuropathology in aged
      VPS35 KI mice, a hallmark of Lewy body pathology in PD. D620N VPS35 expression
      also fails to modify the lethal neurodegenerative phenotype of human
      A53T-alpha-synuclein transgenic mice. Finally, by crossing VPS35 KI and null
      mice, our data demonstrate that a single D620N VPS35 allele is sufficient for
      survival and early maintenance of dopaminergic neurons, indicating that the D620N
      VPS35 protein is fully functional. Our data raise the tantalizing possibility of 
      a pathogenic interplay between mutant VPS35 and tau for inducing
      neurodegeneration in PD.
CI  - Copyright (c) 2019 the Author(s). Published by PNAS.
FAU - Chen, Xi
AU  - Chen X
AD  - Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids,
      MI 49503.
FAU - Kordich, Jennifer K
AU  - Kordich JK
AD  - Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids,
      MI 49503.
FAU - Williams, Erin T
AU  - Williams ET
AD  - Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids,
      MI 49503.
FAU - Levine, Nathan
AU  - Levine N
AD  - Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids,
      MI 49503.
FAU - Cole-Strauss, Allyson
AU  - Cole-Strauss A
AD  - Department of Translational Science and Molecular Medicine, Michigan State
      University, Grand Rapids, MI 49503.
FAU - Marshall, Lee
AU  - Marshall L
AD  - Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids,
      MI 49503.
FAU - Labrie, Viviane
AU  - Labrie V
AD  - Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids,
      MI 49503.
AD  - Division of Psychiatry and Behavioral Medicine, College of Human Medicine,
      Michigan State University, Grand Rapids, MI 49503.
FAU - Ma, Jiyan
AU  - Ma J
AUID- ORCID: http://orcid.org/0000-0001-7150-1898
AD  - Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids,
      MI 49503.
FAU - Lipton, Jack W
AU  - Lipton JW
AD  - Department of Translational Science and Molecular Medicine, Michigan State
      University, Grand Rapids, MI 49503.
FAU - Moore, Darren J
AU  - Moore DJ
AD  - Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids,
      MI 49503; Darren.Moore@vai.org.
LA  - eng
GR  - R01 NS105432/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20190306
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
PMC - PMC6431187
OTO - NOTNLM
OT  - Parkinson's disease
OT  - animal model
OT  - neurodegeneration
OT  - retromer
OT  - tau
COIS- The authors declare no conflict of interest.
EDAT- 2019/03/08 06:00
MHDA- 2019/03/08 06:00
CRDT- 2019/03/08 06:00
PHST- 2019/03/08 06:00 [pubmed]
PHST- 2019/03/08 06:00 [medline]
PHST- 2019/03/08 06:00 [entrez]
AID - 1814909116 [pii]
AID - 10.1073/pnas.1814909116 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5765-5774. doi:
      10.1073/pnas.1814909116. Epub 2019 Mar 6.