title: MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin.
abstract: 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.DOI: http://dx.doi.org/10.7554/eLife.01958.001.
authors.affiliation: Department of Neurology, University of California, Los Angeles, Los Angeles, United States Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Jina
authors.initials: J
authors.lastname: Yun
authors.affiliation: Synaptic Functions Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
authors.forename: Rajat
authors.initials: R
authors.lastname: Puri
authors.affiliation: Department of Neurology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Neurology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lizzio
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, United States.
authors.forename: Chunlai
authors.initials: C
authors.lastname: Wu
authors.affiliation: Synaptic Functions Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
authors.forename: Zu-Hang
authors.initials: ZH
authors.lastname: Sheng
authors.affiliation: Department 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 States mingfly@ucla.edu.
authors.forename: Ming
authors.initials: M
authors.lastname: Guo
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002540:Cerebral Cortex / Q000201:enzymology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D063306:Mitophagy; D009154:Mutation; D009474:Neurons / Q000201:enzymology; D010641:Phenotype; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C527117:Marf protein, Drosophila; C529067:MUL1 protein, human; C000602565:mitochondrial ubiquitin ligase 1, Drosophila; C111567:parkin protein; C534484:PINK1 protein, Drosophila; C487430:park protein, Drosophila
keywords: MUL1; PINK1; Parkinson's disease; mitochondria; parkin; ubiquitin ligase