Abstract
AbstractAlthough most cases of Parkinson’s disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of PD. A surprising number of familial PD-linked genes and PD risk genes are involved in intracellular trafficking and protein degradation. Recessive loss-of-function mutations inATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. FamilialATP13A2mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome (KRS), hereditary spastic paraplegias (HSPs), neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis (ALS). Given the severe effects ofATP13A2mutations in humans, it is surprising thatATP13A2knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages. This discrepancy between human subjects and rodents makes it challenging to study the neuropathological effects of ATP13A2 lossin vivo. Germline deletion ofATP13A2in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deletedATP13A2in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditionalloxP-flankedATP13A2KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onsetATP13A2KO also recreates many of the phenotypes observed in aged germlineATP13A2KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion ofATP13A2in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a usefulin vivomodel ofATP13A2-related neurodegenerative diseases.
Publisher
Cold Spring Harbor Laboratory