Pathogenic insights to Parkin-linked model mice

Abstract

In 2018, we summarized Parkin mutation analysis over the 20 years since its discovery. As a strategy for treating Parkinson’s disease (PD), disease-modifying therapies based on the overall picture of PD, including pathological studies of hereditary PD, have been developed. With the discovery of Parkin, research on PD accelerated explosively around the world. Several PD mouse models were generated to investigate the pathology of PD. Recently, we reported dopaminergic neuron–specific autophagy-deficient mice as a model of sporadic PD. These mice exhibit Lewy pathology and motor dysfunction, and provide in vivo evidence for Lewy body formation. In these animals, synuclein deposition is preceded by p62, resulting in the formation of inclusions containing both proteins. The number and size of these inclusions increase gradually with aging. Consequently, dopaminergic (DA) neuron loss and motor dysfunction are observed in 120-week-old mice. To assess the critical role of Parkin in vivo, we characterized Parkin-knockout mice over a long period of time. At the age of 110 weeks, Parkin-knockout mice exhibited locomotor impairments, including hindlimb defects and neuronal loss, and fragmented mitochondria with abnormal internal structures accumulated in their DA neurons. Age-related motor dysfunction and damaged mitochondria were observed in Parkin-deficient mice.