Title

Rodent Models of Autosomal Recessive Parkinson Disease

Abstract

Using traditional linkage analysis and positional cloning, mutations in genes encoding PARKIN, PINK1, and DJ-1 have been causally associated with the autosomal recessive Parkinson disease (PD) variants PARK2, PARK6, and PARK7, respectively. Traditional germline knock-out models targeting PARKIN, PINK1, and DJ-1 have failed to recapitulate the preferential affection of the substantia nigra pars compacta by core features of late-stage PD, particularly the formation of classical Lewy body and Lewy neurite protein aggregates and the selective loss of dopaminergic neurons, which result in the classical phenotype of deficient spontaneous locomotion in PD. However, in vivo and in vitro studies using knock-out, knock-down, and overexpression have shown a role for these proteins in stress-response and quality-control, particularly in the autophagic degradation of dysfunctional mitochondria as a crucial pathobiological feature of Parkinsonism. Although face validity has been limited to date, rodent PD models are improving, by combining stressors with the absence of stress-response, by using conditional knock-outs, and by overexpressing dominant-negative factors. Rodent models will be crucial to understand the cell-type specific neurodegeneration in PD and to identify disease preventative treatments that target central pathogenic processes rather than providing only symptomatic benefit. In this chapter, we review rodent models for three recessive forms of PD and a variety of multiplex mutants that have yielded important insights into the altered biology of mitochondria in PD.

Publication Title

Movement Disorders: Genetics and Models: Second Edition

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