Journal
CELL REPORTS
Volume 29, Issue 4, Pages 920-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.09.029
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Funding
- Monument Trust Discovery Award from Parkinson's UK [J-1403]
- Joint Programs in Neurodegeneration (JPND) funding from the Medical Research Council [MR/N029453/1]
- MRC [MR/N029453/1, MR/L023784/2, MR/P007058/1, G0700932, MR/K013866/1, MC_EX_MR/P502005/1, MR/J004324/1] Funding Source: UKRI
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Parkinson's disease (PD) is characterized by the death of dopamine neurons in the substantia nigra pars compacta (SNc) and accumulation of alpha-synuclein. Impaired autophagy has been implicated and activation of autophagy proposed as a treatment strategy. Wegenerate a human alpha-synuclein-expressing mouse model of PD with macroautophagic failure in dopamine neurons to understand the interaction between impaired macroautophagy and alpha-synuclein. We find that impaired macroautophagy generates p62-positive inclusions and progressive neuron loss in the SNc. Despite this parkinsonian pathology, motor phenotypes accompanying human alpha-synuclein overexpression actually improve with impaired macroautophagy. Real-time fast-scan cyclic voltammetry reveals that macroautophagy impairment in dopamine neurons increases evoked extracellular concentrations of dopamine, reduces dopamine uptake, and relieves paired-stimulus depression. Our findings show that impaired macroautophagy paradoxically enhances dopamine neurotransmission, improving movement while worsening pathology, suggesting that changes to dopamine synapse function compensate for and conceal the underlying PD pathogenesis, with implications for therapies that target autophagy.
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