Parkin-deficient Mice Exhibit Nigrostriatal Deficits but Not Loss of Dopaminergic Neurons

Matthew S Goldberg,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-Françoise Chesselet,Nigel T Maidment,Michael S Levine,Jie Shen

doi:10.1074/jbc.m308947200

Matthew S Goldberg, Sheila M Fleming + Show 14 more

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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.

Highlights

Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson’s disease
The clinical manifestations of Parkinson’s disease (PD) are due to progressive degeneration of dopaminergic neurons in the pars compacta of the substantia nigra (SN) that give rise to the nigrostriatal pathway, causing dopamine (DA) depletion in the striatum, where it is required for normal motor function
The recent identification of genes linked to familial forms of PD (FPD) makes it possible to investigate the pathogenic mechanism by employing genetic approaches (4 – 6)

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Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson’s disease. Western analysis using an antiserum raised against the C-terminal region of parkin confirmed the absence of parkin in parkinϪ/Ϫ mice (Fig. 1F), and ruled out the presence of possible parkin fragments initiated from in-frame ATGs downstream of exon 3, consistent with the notion that reinitiation of translation following a sizable open reading frame is highly unlikely [34].

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