Impairment of Macroautophagy in Dopamine Neurons Has Opposing Effects on Parkinsonian Pathology and Behavior

Parkinson’s disease (PD) is characterized by the death of dopamine neurons in the substantia nigra pars compacta (SNc) and accumulation of α-synuclein. Impaired autophagy has been implicated and activation of autophagy proposed as a treatment strategy. We generate a human α-synuclein-expressing mouse model of PD with macroautophagic failure in dopamine neurons to understand the interaction between impaired macroautophagy and α-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 α-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. [Display omitted] •Impaired macroautophagy in DA neurons leads to p62+ inclusions and DA neuron death•Macroautophagy impairment increases evoked extracellular DA and reduces DA uptake•Impaired macroautophagy improves human α-synuclein overexpression motor phenotypes•Paradox of enhanced DA neurotransmission but increased neuropathology in PD model Hunn et al. use mouse models to uncover a complex relationship between macroautophagy, cellular neuropathology, dopamine neurotransmission, and Parkinsonian phenotypes. Paradoxically, impaired macroautophagy enhances dopamine neurotransmission and improves movement while worsening cellular pathology, with implications for therapies that target autophagy.