Abstract
Vacuolar protein sorting 35 (VPS35) is a core component of the retromer complex, crucial to endosomal protein sorting and intracellular trafficking. We recently linked a mutation in VPS35 (p.D620N) to familial parkinsonism. Here, we characterize human VPS35 and retromer function in mature murine neuronal cultures and investigate neuron-specific consequences of the p.D620N mutation. We find VPS35 localizes to dendritic spines and is involved in the trafficking of excitatory AMPA-type glutamate receptors (AMPARs). Fundamental neuronal processes, including excitatory synaptic transmission, AMPAR surface expression and synaptic recycling are altered by VPS35 overexpression. VPS35 p.D620N acts as a loss-of-function mutation with respect to VPS35 activity regulating synaptic transmission and AMPAR recycling in mouse cortical neurons and dopamine neuron-like cells produced from induced pluripotent stem cells of human p.D620N carriers. Such perturbations to synaptic function likely produce chronic pathophysiological stress upon neuronal circuits that may contribute to neurodegeneration in this, and other, forms of Parkinsonism.
| Original language | English |
|---|---|
| Journal | Human Molecular Genetics |
| Volume | 24 |
| Issue number | 6 |
| Pages (from-to) | 1691-1703 |
| Number of pages | 13 |
| ISSN | 0964-6906 |
| DOIs | |
| Publication status | Published - 01.01.2015 |
Funding
We thank the Province of British Columbia, LifeLabs and Genome BC for Leading Edge Endowment Funds for the Dr Donald Rix BC Leadership Chair (M.J.F.), and the CAN team and collaborators for technical and material support. Special thanks to H. Mcbride, J. Bonifacino and A.M Craig for kindly providing reagents. This work was directly supported by the Canada Institutes of Health Research (MOP 119347; to M.J.F., A.M.) and the Cundill Foundation (M.J.F.). Infrastructure for the Centre for Applied Neurogenetics and Translation Neuroscience (CAN) is supported through the Canada Excellence Research Chairs program (M.J.F.) and Canada Foundation for Innovation (M.J.F.). L.M. is supported by a CIHR fellowship. C.K. is supported by the DFG (KL 1134/11-1) and by the Hermann and Lilly Schilling Foundation.
