RT Journal Article
SR Electronic
T1 Surface GluA1 and glutamatergic transmission are increased in cortical neurons of a VPS35 D620N knock-in mouse model of parkinsonism and altered by LRRK2 kinase inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.18.427223
DO 10.1101/2021.01.18.427223
A1 Chelsie A Kadgien
A1 Anusha Kamesh
A1 Jaskaran Khinda
A1 Li Ping Cao
A1 Jesse Fox
A1 Matthew J Farrer
A1 Austen J Milnerwood
YR 2021
UL http://biorxiv.org/content/early/2021/01/19/2021.01.18.427223.abstract
AB Vacuolar protein sorting 35 (VPS35) regulates receptor recycling from endosomes. A missense mutation in VPS35 (D620N) leads to autosomal-dominant, late-onset Parkinson’s disease. Here, we use a VPS35 D620N knock-in mouse to study the neurobiology of this mutation. In brain tissue, we confirm previous findings that the mutation results in reduced binding of VPS35 with WASH-complex member FAM21, and robustly elevated phosphorylation of the LRRK2 kinase substrate Rab10. In cultured cortical neurons, the mutation results in increased endosomal recycling protein density (VPS35-FAM21 co-clusters and Rab11 clusters), glutamate release, and GluA1 surface expression. LRRK2 kinase inhibition exerted genotype-specific effects on GluA1 surface expression, but did not impact glutamate release phenotypes. These results improve our understanding of the early effects of the D620N mutation on cellular functions that are specific to neurons. These observations provide candidate pathophysiological pathways that may drive eventual transition to late-stage parkinsonism in VPS35 families, and support a synaptopathy model of neurodegeneration.