Disrupted Autophagy Leads to Dopaminergic Axon and Dendrite Degeneration and Promotes Presynaptic Accumulation of α-Synuclein and LRRK2 in the Brain
Open Access
- 30 May 2012
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 32 (22), 7585-7593
- https://doi.org/10.1523/jneurosci.5809-11.2012
Abstract
Parkinson's disease (PD) is characterized pathologically by the formation of ubiquitin and α-synuclein (α-syn)-containing inclusions (Lewy bodies), dystrophic dopamine (DA) terminals, and degeneration of midbrain DA neurons. The precise molecular mechanisms underlying these pathological features remain elusive. Accumulating evidence has implicated dysfunctional autophagy, the cell self-digestion and neuroprotective pathway, as one of the pathogenic systems contributing to the development of idiopathic PD. Here we characterize autophagy-deficient mouse models and providein vivoevidence for the potential role that impaired autophagy plays in pathogenesis associated with PD. Cell-specific deletion of essential autophagy geneAtg7in midbrain DA neurons causes delayed neurodegeneration, accompanied by late-onset locomotor deficits. In contrast,Atg7-deficient DA neurons in the midbrain exhibit early dendritic and axonal dystrophy, reduced striatal dopamine content, and the formation of somatic and dendritic ubiquitinated inclusions in DA neurons. Furthermore, whole-brain-specific loss ofAtg7leads to presynaptic accumulation of α-syn and LRRK2 proteins, which are encoded by two autosomal dominantly inherited PD-related genes. Our results suggest that disrupted autophagy may be associated with enhanced levels of endogenous α-syn and LRRK2 proteinsin vivo. Our findings implicate dysfunctional autophagy as one of the failing cellular mechanisms involved in the pathogenesis of idiopathic PD.Keywords
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