MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin
Parkinson's disease (PD) genes PINK1 and parkin act in a common pathway that regulates mitochondrial integrity and quality. Identifying new suppressors of the pathway is important for finding new therapeutic strategies. In this study, we show that MUL1 suppresses PINK1 or parkin mutant phenotyp...
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doaj-91247786dda84072a177d285e71467fb2021-05-04T23:11:05ZengeLife Sciences Publications LtdeLife2050-084X2014-06-01310.7554/eLife.01958MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkinJina Yun0Rajat Puri1Huan Yang2Michael A Lizzio3Chunlai Wu4Zu-Hang Sheng5Ming Guo6Department of Neurology, University of California, Los Angeles, Los Angeles, United States; Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United StatesSynaptic Functions Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United StatesDepartment of Neurology, University of California, Los Angeles, Los Angeles, United StatesDepartment of Neurology, University of California, Los Angeles, Los Angeles, United StatesNeuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, United StatesSynaptic Functions Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United StatesDepartment of Neurology, University of California, Los Angeles, Los Angeles, United States; Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States; Brain Research Institute, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United StatesParkinson's disease (PD) genes PINK1 and parkin act in a common pathway that regulates mitochondrial integrity and quality. Identifying new suppressors of the pathway is important for finding new therapeutic strategies. In this study, we show that MUL1 suppresses PINK1 or parkin mutant phenotypes in Drosophila. The suppression is achieved through the ubiquitin-dependent degradation of Mitofusin, which itself causes PINK1/parkin mutant-like toxicity when overexpressed. We further show that removing MUL1 in PINK1 or parkin loss-of-function mutant aggravates phenotypes caused by loss of either gene alone, leading to lethality in flies and degeneration in mouse cortical neurons. Together, these observations show that MUL1 acts in parallel to the PINK1/parkin pathway on a shared target mitofusin to maintain mitochondrial integrity. The MUL1 pathway compensates for loss of PINK1/parkin in both Drosophila and mammals and is a promising therapeutic target for PD.https://elifesciences.org/articles/01958Parkinson's diseasemitochondriaPINK1parkinubiquitin ligaseMUL1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jina Yun Rajat Puri Huan Yang Michael A Lizzio Chunlai Wu Zu-Hang Sheng Ming Guo |
spellingShingle |
Jina Yun Rajat Puri Huan Yang Michael A Lizzio Chunlai Wu Zu-Hang Sheng Ming Guo MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin eLife Parkinson's disease mitochondria PINK1 parkin ubiquitin ligase MUL1 |
author_facet |
Jina Yun Rajat Puri Huan Yang Michael A Lizzio Chunlai Wu Zu-Hang Sheng Ming Guo |
author_sort |
Jina Yun |
title |
MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin |
title_short |
MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin |
title_full |
MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin |
title_fullStr |
MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin |
title_full_unstemmed |
MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin |
title_sort |
mul1 acts in parallel to the pink1/parkin pathway in regulating mitofusin and compensates for loss of pink1/parkin |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2014-06-01 |
description |
Parkinson's disease (PD) genes PINK1 and parkin act in a common pathway that regulates mitochondrial integrity and quality. Identifying new suppressors of the pathway is important for finding new therapeutic strategies. In this study, we show that MUL1 suppresses PINK1 or parkin mutant phenotypes in Drosophila. The suppression is achieved through the ubiquitin-dependent degradation of Mitofusin, which itself causes PINK1/parkin mutant-like toxicity when overexpressed. We further show that removing MUL1 in PINK1 or parkin loss-of-function mutant aggravates phenotypes caused by loss of either gene alone, leading to lethality in flies and degeneration in mouse cortical neurons. Together, these observations show that MUL1 acts in parallel to the PINK1/parkin pathway on a shared target mitofusin to maintain mitochondrial integrity. The MUL1 pathway compensates for loss of PINK1/parkin in both Drosophila and mammals and is a promising therapeutic target for PD. |
topic |
Parkinson's disease mitochondria PINK1 parkin ubiquitin ligase MUL1 |
url |
https://elifesciences.org/articles/01958 |
work_keys_str_mv |
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