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Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia
Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mech...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131106/ https://www.ncbi.nlm.nih.gov/pubmed/34002696 http://dx.doi.org/10.7554/eLife.68039 |
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author | Aguilar, Jenny I Cheng, Mary Hongying Font, Josep Schwartz, Alexandra C Ledwitch, Kaitlyn Duran, Amanda Mabry, Samuel J Belovich, Andrea N Zhu, Yanqi Carter, Angela M Shi, Lei Kurian, Manju A Fenollar-Ferrer, Cristina Meiler, Jens Ryan, Renae Monique Mchaourab, Hassane S Bahar, Ivet Matthies, Heinrich JG Galli, Aurelio |
author_facet | Aguilar, Jenny I Cheng, Mary Hongying Font, Josep Schwartz, Alexandra C Ledwitch, Kaitlyn Duran, Amanda Mabry, Samuel J Belovich, Andrea N Zhu, Yanqi Carter, Angela M Shi, Lei Kurian, Manju A Fenollar-Ferrer, Cristina Meiler, Jens Ryan, Renae Monique Mchaourab, Hassane S Bahar, Ivet Matthies, Heinrich JG Galli, Aurelio |
author_sort | Aguilar, Jenny I |
collection | PubMed |
description | Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD. |
format | Online Article Text |
id | pubmed-8131106 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-81311062021-05-19 Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia Aguilar, Jenny I Cheng, Mary Hongying Font, Josep Schwartz, Alexandra C Ledwitch, Kaitlyn Duran, Amanda Mabry, Samuel J Belovich, Andrea N Zhu, Yanqi Carter, Angela M Shi, Lei Kurian, Manju A Fenollar-Ferrer, Cristina Meiler, Jens Ryan, Renae Monique Mchaourab, Hassane S Bahar, Ivet Matthies, Heinrich JG Galli, Aurelio eLife Neuroscience Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD. eLife Sciences Publications, Ltd 2021-05-18 /pmc/articles/PMC8131106/ /pubmed/34002696 http://dx.doi.org/10.7554/eLife.68039 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (https://creativecommons.org/publicdomain/zero/1.0/) . |
spellingShingle | Neuroscience Aguilar, Jenny I Cheng, Mary Hongying Font, Josep Schwartz, Alexandra C Ledwitch, Kaitlyn Duran, Amanda Mabry, Samuel J Belovich, Andrea N Zhu, Yanqi Carter, Angela M Shi, Lei Kurian, Manju A Fenollar-Ferrer, Cristina Meiler, Jens Ryan, Renae Monique Mchaourab, Hassane S Bahar, Ivet Matthies, Heinrich JG Galli, Aurelio Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia |
title | Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia |
title_full | Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia |
title_fullStr | Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia |
title_full_unstemmed | Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia |
title_short | Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia |
title_sort | psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile parkinsonism-dystonia |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131106/ https://www.ncbi.nlm.nih.gov/pubmed/34002696 http://dx.doi.org/10.7554/eLife.68039 |
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