Munsie, L N, Milnerwood, A J, Seibler, P, Beccano-Kelly, D A  ORCID: https://orcid.org/0000-0003-3592-8354, Tatarnikov, I, Khinda, J, Volta, M, Kadgien, C, Cao, L P, Tapia, L, Klein, C and Farrer, M J
2014.
Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson's disease VPS35 mutation p.D620N.
Human Molecular Genetics
24
(6)
, pp. 1691-1703.
10.1093/hmg/ddu582
|
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.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | Published |
| Schools: | Medicine |
| Publisher: | Oxford University Press |
| ISSN: | 0964-6906 |
| Last Modified: | 10 Nov 2022 11:20 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/150136 |
Citation Data
Cited 96 times in Scopus. View in Scopus. Powered By Scopus® Data
Actions (repository staff only)
 |
Edit Item |
Altmetric
Altmetric
Cardiff University Information Services