Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons - PubMed (original) (raw)

. 2003 Oct 31;278(44):43628-35.

doi: 10.1074/jbc.M308947200. Epub 2003 Aug 20.

Sheila M Fleming, James J Palacino, Carlos Cepeda, Hoa A Lam, Anushree Bhatnagar, Edward G Meloni, Nanping Wu, Larry C Ackerson, Gloria J Klapstein, Mahadevan Gajendiran, Bryan L Roth, Marie-Francoise Chesselet, Nigel T Maidment, Michael S Levine, Jie Shen

Affiliations

Free article

Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons

Matthew S Goldberg et al. J Biol Chem. 2003.

Free article

Abstract

Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease. To investigate the pathogenic mechanism by which loss of parkin function causes Parkinson's disease, we generated a mouse model bearing a germline disruption in parkin. Parkin-/- mice are viable and exhibit grossly normal brain morphology. Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin-/- mice. Intracellular recordings of medium-sized striatal spiny neurons showed that greater currents are required to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of parkin. Furthermore, parkin-/- mice exhibit deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway. The number of dopaminergic neurons in the substantia nigra of parkin-/- mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease. Steady-state levels of CDCrel-1, synphilin-1, and alpha-synuclein, which were identified previously as substrates of the E3 ubiquitin ligase activity of parkin, are unaltered in parkin-/- brains. Together these findings provide the first evidence for a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role of parkin in the survival of nigral neurons in mice.

PubMed Disclaimer

Publication types

MeSH terms

Substances

LinkOut - more resources