Abstract
BackgroundAutophagy is intensively studied in cancer, metabolic and neurodegenerative diseases, but little is known about its role in pathological conditions linked to altered neurotransmission. We examined the involvement of autophagy in levodopa (l‐dopa)‐induced dyskinesia, a frequent motor complication developed in response to standard dopamine replacement therapy in parkinsonian patients.MethodsWe used mouse and non‐human primate models of Parkinson's disease to examine changes in autophagy associated with chronic l‐dopa administration and to establish a causative link between impaired autophagy and dyskinesia.ResultsWe found that l‐dopa‐induced dyskinesia is associated with accumulation of the autophagy‐specific substrate p62, a marker of autophagy deficiency. Increased p62 was observed in a subset of projection neurons located in the striatum and depended on l‐dopa‐mediated activation of dopamine D1 receptors, and mammalian target of rapamycin. Inhibition of mammalian target of rapamycin complex 1 with rapamycin counteracted the impairment of autophagy produced by l‐dopa, and reduced dyskinesia. The anti‐dyskinetic effect of rapamycin was lost when autophagy was constitutively suppressed in D1 receptor‐expressing striatal neurons, through inactivation of the autophagy‐related gene protein 7.ConclusionsThese findings indicate that augmented responsiveness at D1 receptors leads to dysregulated autophagy, and results in the emergence of l‐dopa‐induced dyskinesia. They further suggest the enhancement of autophagy as a therapeutic strategy against dyskinesia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Highlights
Disruption of dopamine transmission is a cardinal feature of Parkinson’s disease (PD), a common neurodegenerative disorder characterized by severe motor impairment
Increased p62 protein levels were not paralleled by enhanced p62 mRNA (Fig. 1C), indicating that the effect of L-dopa was exerted via reduced degradation, rather than augmented transcription
This study shows that in mouse and non-human primates (NHP) models of PD, dyskinesia, a serious motor disorder caused by administration of standard anti-parkinsonian medications, is associated with molecular changes linked to impaired autophagy
Summary
Disruption of dopamine transmission is a cardinal feature of Parkinson’s disease (PD), a common neurodegenerative disorder characterized by severe motor impairment. Administration of rapamycin, a selective inhibitor of the mTOR complex 1 (mTORC1), reduces abnormal involuntary movements (AIMs), a surrogate marker of LID, in rodent models of PD.[6,8] mTORC1 plays a key role in the control of protein synthesis, via activation of downstream effector targets that promote initiation of translation and elongation of mRNA,[9] as well as upregulation of ribosomal proteins and translation factors.[10] Another essential role of mTORC1 pertains to its ability to regulate autophagy, an intracellular pathway involved in lysosomal degradation of protein aggregates and pathogens, as well as in cellular processes such as phagocytosis, secretion, and exocytosis.[11] Activation of mTORC1 inhibits autophagy through phosphorylation of the Unc-51like kinase 1 (Ulk1), a mammalian homolog of the autophagyrelated gene protein (Atg) 1 originally described in yeast.[12] mTORC1-mediated phosphorylation at S757 prevents Ulk[1] forming a core complex with other Atg required for the generation of the autophagosome.[13,14] Changes in autophagy can be monitored by measuring the levels of the specific substrate p62 ( named sequestosome 1). P62 interacts with polyubiquitinated proteins and is targeted to the autophagosome, where it is eliminated together with its cargo by lysosomal degradation.[15,16] Accumulation of p62 is regarded as a marker of impaired autophagy.[15,16]
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