| First Author | Subramaniam M | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 41 | Pages | 13586-99 |
| PubMed ID | 25297088 | Mgi Jnum | J:216589 |
| Mgi Id | MGI:5609073 | Doi | 10.1523/JNEUROSCI.5069-13.2014 |
| Citation | Subramaniam M, et al. (2014) Mutant alpha-synuclein enhances firing frequencies in dopamine substantia nigra neurons by oxidative impairment of A-type potassium channels. J Neurosci 34(41):13586-99 |
| abstractText | Parkinson disease (PD) is an alpha-synucleinopathy resulting in the preferential loss of highly vulnerable dopamine (DA) substantia nigra (SN) neurons. Mutations (e.g., A53T) in the alpha-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 alpha-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 alpha-synuclein that might be useful as a novel biomarker for the "DA system at risk" before the onset of neurodegeneration in PD. |
