Abstract
Mutations in PARK2 (parkin) can result in Parkinson’s disease (PD). Parkin shares a bidirectional promoter with parkin coregulated gene (PACRG) and the transcriptional start sites are separated by only ~200 bp. Bidirectionally regulated genes have been shown to function in common biological pathways. Mice lacking parkin have largely failed to recapitulate the dopaminergic neuronal loss and movement impairments seen in individuals with parkin-mediated PD. We aimed to investigate the function of PACRG and test the hypothesis that parkin and PACRG function in a common pathway by generating and characterizing two novel knockout mouse lines harbouring loss of both parkin and Pacrg or Pacrg alone. Successful modification of the targeted allele was confirmed at the genomic, transcriptional and steady state protein levels for both genes. At 18–20 months of age, there were no significant differences in the behaviour of parental and mutant lines when assessed by openfield, rotarod and balance beam. Subsequent neuropathological examination suggested there was no gross abnormality of the dopaminergic system in the substantia nigra and no significant difference in the number of dopaminergic neurons in either knockout model compared to wildtype mice.
Highlights
Parkinson’s disease (PD) is an age associated progressive neurodegenerative movement disorder that is estimated to effect over 5 million people worldwide[1]
An increased risk of PD has been identified in individuals who live in agricultural or rural areas, in particular farmers, which is thought to be related to pesticide exposure[4]
The causative associations of pesticides to PD aetiology are limited, perhaps owing to the heterogeneous nature of the disease, long-term and low dose pesticide exposure is neurotoxic to dopaminergic neurons in a number of model systems[5]
Summary
Parkinson’s disease (PD) is an age associated progressive neurodegenerative movement disorder that is estimated to effect over 5 million people worldwide[1]. Evidence supporting a genetic association of PACRG mutation and PD has not been reported[26], the protein has been shown to be a component of Lewy bodies in PD27,28 and steady state levels of parkin and PACRG have been shown to be inversely correlated with alpha-synuclein accumulation in the astrocytes of individuals with PD29. These observations suggest PACRG may be functionally coupled to parkin and involved in the cellular processes that characterizes neurodegeneration
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