Abstract
AbstractParkinson’s disease (PD) is a common neurodegenerative motor disorder characterized in part by neuropathological lesions in the nigrostriatal pathway. Loss of function mutations in Auxilin, the major neuronal clathrin uncoating protein, cause an aggressive form of juvenile onset PD. How mutations in Auxilin cause PD, is currently not understood. Here, we generated a novel mouse model carrying an endogenous pathogenic Auxilin mutation that phenocopies neurological features observed in patients, including motor impairments and seizures. Unbiased mapping of the Auxilin interactome identified synaptic and Golgi-resident clathrin adaptor proteins as novel interactors. Impaired clathrin-mediated trafficking in mutant Auxilin mice, both at the Golgi and the synapse, results in neuropathological lesions in the nigrostriatal pathway. Collectively, these results provide molecular mechanisms of PD pathogenesis in Auxilin mutation carriers, reinforcing a key role for clathrin-mediated trafficking in PD, and expand our understanding of the cellular function of Auxilin.
Publisher
Cold Spring Harbor Laboratory
Reference63 articles.
1. Parkinson's disease
2. Pathways to parkinsonism redux: convergent pathobiological mechanisms in genetics of Parkinson’s disease;Hum. Mol. Genet,2015
3. The genetics of Parkinson's syndromes: a critical review
4. A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism;PLoS One,2012
5. D
NAJC
6
Mutations Associated With Early-Onset Parkinson's Disease
Cited by
10 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献