PT  - JOURNAL ARTICLE
AU  - Mahalakshmi Subramaniam
AU  - Daniel Althof
AU  - Suzana Gispert
AU  - Jochen Schwenk
AU  - Georg Auburger
AU  - Akos Kulik
AU  - Bernd Fakler
AU  - Jochen Roeper
TI  - Mutant α-Synuclein Enhances Firing Frequencies in Dopamine Substantia Nigra Neurons by Oxidative Impairment of A-Type Potassium Channels
AID  - 10.1523/JNEUROSCI.5069-13.2014
DP  - 2014 Oct 08
TA  - The Journal of Neuroscience
PG  - 13586--13599
VI  - 34
IP  - 41
4099  - http://www.jneurosci.org/content/34/41/13586.short
4100  - http://www.jneurosci.org/content/34/41/13586.full
SO  - J. Neurosci.2014 Oct 08; 34
AB  - Parkinson disease (PD) is an α-synucleinopathy resulting in the preferential loss of highly vulnerable dopamine (DA) substantia nigra (SN) neurons. Mutations (e.g., A53T) in the α-synuclein gene (SNCA) are sufficient to cause PD, but the mechanism of their selective action on vulnerable DA SN neurons is unknown. In a mouse model overexpressing mutant α-synuclein (A53T-SNCA), we identified a SN-selective increase of in vivo firing frequencies in DA midbrain neurons, which was not observed in DA neurons in the ventral tegmental area. 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 α-synuclein that might be useful as a novel biomarker for the “DA system at risk” before the onset of neurodegeneration in PD.