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Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease
Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson’s disease (PD). Here, we utilized auxilin knockout (KO) mice to eluci...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127800/ https://www.ncbi.nlm.nih.gov/pubmed/36920906 http://dx.doi.org/10.1016/j.celrep.2023.112231 |
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author | Vidyadhara, D.J. Somayaji, Mahalakshmi Wade, Nigel Yücel, Betül Zhao, Helen Shashaank, N. Ribaudo, Joseph Gupta, Jyoti Lam, TuKiet T. Sames, Dalibor Greene, Lois E. Sulzer, David L. Chandra, Sreeganga S. |
author_facet | Vidyadhara, D.J. Somayaji, Mahalakshmi Wade, Nigel Yücel, Betül Zhao, Helen Shashaank, N. Ribaudo, Joseph Gupta, Jyoti Lam, TuKiet T. Sames, Dalibor Greene, Lois E. Sulzer, David L. Chandra, Sreeganga S. |
author_sort | Vidyadhara, D.J. |
collection | PubMed |
description | Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson’s disease (PD). Here, we utilized auxilin knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. Auxilin KO mice display cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Significantly, treatment with L-DOPA ameliorated motor deficits. Unbiased proteomic and neurochemical analyses of auxilin KO brains indicated dopamine dyshomeostasis. We validated these findings by demonstrating slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. Defective SV protein sorting and elevated synaptic autophagy also contribute to ineffective dopamine sequestration and compartmentalization, ultimately leading to neurodegeneration. This study provides insights into how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD. |
format | Online Article Text |
id | pubmed-10127800 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
record_format | MEDLINE/PubMed |
spelling | pubmed-101278002023-04-25 Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease Vidyadhara, D.J. Somayaji, Mahalakshmi Wade, Nigel Yücel, Betül Zhao, Helen Shashaank, N. Ribaudo, Joseph Gupta, Jyoti Lam, TuKiet T. Sames, Dalibor Greene, Lois E. Sulzer, David L. Chandra, Sreeganga S. Cell Rep Article Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson’s disease (PD). Here, we utilized auxilin knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. Auxilin KO mice display cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Significantly, treatment with L-DOPA ameliorated motor deficits. Unbiased proteomic and neurochemical analyses of auxilin KO brains indicated dopamine dyshomeostasis. We validated these findings by demonstrating slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. Defective SV protein sorting and elevated synaptic autophagy also contribute to ineffective dopamine sequestration and compartmentalization, ultimately leading to neurodegeneration. This study provides insights into how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD. 2023-03-28 2023-03-14 /pmc/articles/PMC10127800/ /pubmed/36920906 http://dx.doi.org/10.1016/j.celrep.2023.112231 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article Vidyadhara, D.J. Somayaji, Mahalakshmi Wade, Nigel Yücel, Betül Zhao, Helen Shashaank, N. Ribaudo, Joseph Gupta, Jyoti Lam, TuKiet T. Sames, Dalibor Greene, Lois E. Sulzer, David L. Chandra, Sreeganga S. Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease |
title | Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease |
title_full | Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease |
title_fullStr | Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease |
title_full_unstemmed | Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease |
title_short | Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease |
title_sort | dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated parkinson’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127800/ https://www.ncbi.nlm.nih.gov/pubmed/36920906 http://dx.doi.org/10.1016/j.celrep.2023.112231 |
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