Impairment of Macroautophagy in Dopamine Neurons Has Opposing Effects on Parkinsonian Pathology and Behavior
Benjamin H.M. Hunn,
Siv Vingill,
Sarah Threlfell,
Javier Alegre-Abarrategui,
Morgane Magdelyns,
Thierry Deltheil,
Nora Bengoa-Vergniory,
Peter L. Oliver,
Milena Cioroch,
Natalie M. Doig,
David M. Bannerman,
Stephanie J. Cragg,
Richard Wade-Martins
Affiliations
Benjamin H.M. Hunn
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
Siv Vingill
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
Sarah Threlfell
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
Javier Alegre-Abarrategui
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
Morgane Magdelyns
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK; Université Catholique de Louvain, Louvain-la-neuve, Region Wallone 1348, Belgium
Thierry Deltheil
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
Nora Bengoa-Vergniory
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
Peter L. Oliver
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK; Medical Research Council Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK
Milena Cioroch
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
Natalie M. Doig
Medical Research Council Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3TH, UK
David M. Bannerman
Department of Experimental Psychology, University of Oxford, Oxford OX1 3TA, UK
Stephanie J. Cragg
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
Richard Wade-Martins
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK; Corresponding author
Summary: 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. : 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. Keywords: Parkinson’s disease, autophagy, pathology, dopamine, neurotransmission, behavior, mouse models
