Ablation of Mitochondrial RCC1-L Induces Nigral Dopaminergic Neurodegeneration and Parkinsonian-like Motor Symptoms

Abstract

ABSTRACTMitochondrial dysfunction has been linked to both idiopathic and familial forms of Parkinson’s disease (PD). We have previously identified RCC1-like (RCC1L) as a protein of the inner mitochondrial membrane important to mitochondrial fusion. Herein, to test whether deficits in RCC1L mitochondrial function might be involved in PD pathology, we have selectively ablated theRcc1lgene in the dopaminergic (DA) neurons of mice. A PD-like phenotype resulted that includes progressive movement abnormalities, paralleled by progressive degeneration of the nigrostriatal tract. Experimental and control groups were examined at 2, 3-4, and 5-6 months of age. Animals were tested in the open field task to quantify anxiety, exploratory drive, locomotion, and immobility; and in the cylinder test to quantify rearing behavior. Beginning at 3-4 months, both female and maleRcc1lknockout mice show rigid muscles and resting tremor, kyphosis and a growth deficit compared with heterozygous or wild type littermate controls.Rcc1lknockout mice begin showing locomotor impairments at 3-4 months, which progress until 5-6 months of age, at which age theRcc1lknockout mice die. The progressive motor impairments were associated with progressive and significantly reduced tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta (SNc), and dramatic loss of nigral DA projections in the striatum. Dystrophic spherical mitochondria are apparent in the soma of SNc neurons inRcc1lknockout mice as early as 1.5-2.5 months of age and become progressively more pronounced until 5-6 months. Together, the results reveal the RCC1L protein to be essential toin vivomitochondrial function in DA neurons. Further characterization of this mouse model will determine whether it represents a new model forin vivostudy of PD, and the putative role of the humanRCC1Lgene as a risk factor that might increase PD occurrence and severity in humans.