Matches in SemOpenAlex for { <https://semopenalex.org/work/W2920510256> ?p ?o ?g. }
- W2920510256 endingPage "5774" @default.
- W2920510256 startingPage "5765" @default.
- W2920510256 abstract "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 α-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-α-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." @default.
- W2920510256 created "2019-03-11" @default.
- W2920510256 creator A5008171524 @default.
- W2920510256 creator A5022859761 @default.
- W2920510256 creator A5033733203 @default.
- W2920510256 creator A5037205059 @default.
- W2920510256 creator A5038011017 @default.
- W2920510256 creator A5048700113 @default.
- W2920510256 creator A5063334368 @default.
- W2920510256 creator A5067127770 @default.
- W2920510256 creator A5078501123 @default.
- W2920510256 creator A5086118916 @default.
- W2920510256 date "2019-03-06" @default.
- W2920510256 modified "2023-09-29" @default.
- W2920510256 title "Parkinson’s disease-linked <i>D620N VPS35</i> knockin mice manifest tau neuropathology and dopaminergic neurodegeneration" @default.
- W2920510256 cites W1496790952 @default.
- W2920510256 cites W1527671059 @default.
- W2920510256 cites W1530007708 @default.
- W2920510256 cites W1864669235 @default.
- W2920510256 cites W1868577792 @default.
- W2920510256 cites W1953962861 @default.
- W2920510256 cites W1964834461 @default.
- W2920510256 cites W1973911766 @default.
- W2920510256 cites W1983044117 @default.
- W2920510256 cites W1984539680 @default.
- W2920510256 cites W1986628169 @default.
- W2920510256 cites W1989913002 @default.
- W2920510256 cites W1991437616 @default.
- W2920510256 cites W1993201929 @default.
- W2920510256 cites W1999056400 @default.
- W2920510256 cites W2006037420 @default.
- W2920510256 cites W2014397333 @default.
- W2920510256 cites W2025343900 @default.
- W2920510256 cites W2028171714 @default.
- W2920510256 cites W2032481706 @default.
- W2920510256 cites W2039073478 @default.
- W2920510256 cites W2040454459 @default.
- W2920510256 cites W2042213574 @default.
- W2920510256 cites W2045402408 @default.
- W2920510256 cites W2048391838 @default.
- W2920510256 cites W2050786534 @default.
- W2920510256 cites W2054961347 @default.
- W2920510256 cites W2063127941 @default.
- W2920510256 cites W2063690790 @default.
- W2920510256 cites W2063785968 @default.
- W2920510256 cites W2079911954 @default.
- W2920510256 cites W2082214922 @default.
- W2920510256 cites W2099111846 @default.
- W2920510256 cites W2100894616 @default.
- W2920510256 cites W2116002414 @default.
- W2920510256 cites W2123431154 @default.
- W2920510256 cites W2131769515 @default.
- W2920510256 cites W2133954552 @default.
- W2920510256 cites W2141459724 @default.
- W2920510256 cites W2143829960 @default.
- W2920510256 cites W2150669288 @default.
- W2920510256 cites W2156959507 @default.
- W2920510256 cites W2159306546 @default.
- W2920510256 cites W2164390539 @default.
- W2920510256 cites W2185034389 @default.
- W2920510256 cites W2185332753 @default.
- W2920510256 cites W2189621653 @default.
- W2920510256 cites W2212507736 @default.
- W2920510256 cites W2253950023 @default.
- W2920510256 cites W2340446708 @default.
- W2920510256 cites W2512614361 @default.
- W2920510256 cites W2587358277 @default.
- W2920510256 cites W2588340423 @default.
- W2920510256 cites W2724252641 @default.
- W2920510256 cites W2766933124 @default.
- W2920510256 cites W2795359717 @default.
- W2920510256 cites W2802214895 @default.
- W2920510256 cites W2808284168 @default.
- W2920510256 cites W2885962028 @default.
- W2920510256 cites W37005 @default.
- W2920510256 cites W4243195227 @default.
- W2920510256 cites W4362221370 @default.
- W2920510256 cites W47608607 @default.
- W2920510256 cites W49996880 @default.
- W2920510256 doi "https://doi.org/10.1073/pnas.1814909116" @default.
- W2920510256 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6431187" @default.
- W2920510256 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30842285" @default.
- W2920510256 hasPublicationYear "2019" @default.
- W2920510256 type Work @default.
- W2920510256 sameAs 2920510256 @default.
- W2920510256 citedByCount "69" @default.
- W2920510256 countsByYear W29205102562019 @default.
- W2920510256 countsByYear W29205102562020 @default.
- W2920510256 countsByYear W29205102562021 @default.
- W2920510256 countsByYear W29205102562022 @default.
- W2920510256 countsByYear W29205102562023 @default.
- W2920510256 crossrefType "journal-article" @default.
- W2920510256 hasAuthorship W2920510256A5008171524 @default.
- W2920510256 hasAuthorship W2920510256A5022859761 @default.
- W2920510256 hasAuthorship W2920510256A5033733203 @default.
- W2920510256 hasAuthorship W2920510256A5037205059 @default.
- W2920510256 hasAuthorship W2920510256A5038011017 @default.
- W2920510256 hasAuthorship W2920510256A5048700113 @default.