Homozygous mice are viable and fertile, and exhibit grossly normal brain morphology. Western blot analysis using antibody specific to C-terminal sequences indicates the absence of full length gene product. RT-PCR shows that exon 2 splices to exon 4, skipping exon 3 entirely, resulting in a frame shift and a premature stop codon in exon 5. While EGFP transcripts are present, little parkin-EGFP fusion protein is detectable by Western analysis. Homozygous mice have increased extracellular dopamine concentration in the striatum. Further, medium-sized striatal spiny neurons require greater currents to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of the endogenous gene. Homozygotes also exhibit deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway. The numbers of dopaminergic neurons in the substantia nigra, however, are normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease. Homozygous mice and their isolated cells exhibit mitochondrial dysfunction and impaired protection from oxidative stress. Muscle cells isolated from homozygous mice have defective skeletal muscle mitochondrial homeostasis and increased sensitivity to amyloid-beta toxicity. These mice model the exon 3 deletion mutation most common in human autosomal recessive juvenile parkinsonism (AR-JP) patients and may be useful in studies of Parkinson's disease, dopamine regulation, nigrostriatal function, mitochondrial function, and other neurobiological research.
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. Mice with this mutation were originally published on a mixed B6;129S4 genetic background. It should be noted that the phenotype could vary from that originally described. The strain description will be modified as published results become available.
