Loss-of-Function Rodent Models for Parkin and PINK1

Abstract

Parkinson's disease is a common neurodegenerative disorder whose aetiology is not yet fully understood. In the past ten years, the discovery of genes linked to hereditary forms of the disease has impelled the development of animal models. These should lead to the identification of novel pathways that provide insight into the functionality of the proteins involved and the pathogenesis of the sporadic forms of the disease. In particular, loss-of-function mutations in the parkin and PINK1 (phosphatase and tensin homolog (PTEN)-induced kinase 1) genes account for most of the cases of familial autosomal recessive parkinsonism. Both parkin and PINK1 knockout rodent models are now available, which display an overall mild phenotype consisting of a mitochondrial dysfunction together with changes in dopamine metabolism and oxidative stress. However, up till now these models fail to reproduce the main hallmarks of Parkinson's disease: the dopaminergic cell loss in the substantia nigra and the presence of cytoplasmic inclusions, named Lewy bodies, in the remaining dopaminergic neurons. We here review the most important knockout and knockdown rodent models generated so far for these two recessive Parkinson's disease-causing genes. We critically feature their main characteristics and their impact on the research field, and propose some future directions for the study and modelling of the loss of function of parkin and PINK1 in rodents.

Rgs6 is Required for Adult Maintenance of Dopaminergic Neurons in the Ventral Substantia Nigra

“…For example, DJ-1 and PINK1 are two genes whose mutated forms cause PD in an autosomal recessive manner and LRRK2 is the most frequently mutated gene causing PD and it acts in an autosomal-dominant fashion. Pink1 and Lrrk2 mouse null mutants do not however display degeneration of mDA neurons [5] , [35] but a rat model of Pink1 knockout does [8] . Surprisingly, the TH low neurons of Rgs6 −/− vSNc specifically exhibit decreased DJ-1 expression, while Pink1 and Lrrk2 expression is increased in those same neurons ( Fig.…”

Inhibition of the mitochondrial calcium uniporter rescues dopaminergic neurons in pink1−/− zebrafish

“…vertebrates will be challenging due to the absence of dopaminergic neuronal cell loss in Pink1 k/o mice (Oliveras-Salva et al, 2011). Of note, lack of MCU does not protect heart cells against ischemic cell death despite an abolished effect of ischemia on the activation of the mitochondrial permeability transition pore in Mcu À/À mice (Pan et al, 2013).…”

How Mitochondrial Dynamism Orchestrates Mitophagy

“…That has not been the case. Indeed, multiple efforts to ablate PINK1 or Parkin in mice by genetically deleting exons encoding critical protein domains have produced a “negligible neurodegenerative pattern in the (dopaminergic neuron-rich) substantia nigra pars compacta, a region clearly affected in Parkinson’s disease patients” 140 . Even combined deletion of the mouse genes for PINK1, Parkin, and DJ-1 (another gene in which loss-of-function mutations have been causally linked to early Parkinsons disease) has failed to recapitulate the hallmark loss of dopaminergic neurons in the brain 141 .…”