Mutant ?-synuclein enhances firing frequencies in dopamine substantia nigra neurons by oxidative impairment of A-type potassium channels
08.10.2014
Subramaniam M, Althof D, Gispert S, Schwenk J, Auburger G, Kulik A, Fakler B, Roeper J
J Neurosci. 2014 Oct 8;34(41):13586-99.
Parkinson disease (PD) is an alpha-synucleopathy resulting in the preferential loss of vulnerable dopamine (DA) substantia nigra (SN) neurons. Mutations (A53T) in the alpha-synuclein gene (SNCA) are sufficient to cause PD, but the mechanism of their selective action on DA SN neurons is unknown. In a model overexpressing mutant alpha-synuclein (A53T-SNCA) we identified a SN-selective increase of in vivo firing frequences in DA neurons, which was not observed in DA neurons in the VTA. The selective and age-dependent gain-of-function phenotype of A53T-SCNA overexpressing DA SN neurons was in part mediated by an increase of their intrinsic pacemaker frequency caused by a redox-dependent impairment of A-type Kv4.3 potassium channels. This selective enhancement of "stressful pacemaking" of DA SN neurons in vivo defines a functional response to mutant alpha-synuclein that might be useful as a novel biomarker for the "DA system at risk" before the onset of neurodegeneration in PD.
