Mahogunin ring finger 1 suppresses misfolded polyglutamine aggregation and cytotoxicity.
Polyglutamine diseases are a family of inherited neurodegenerative diseases caused by the expansion of CAG repeats within the coding region of target genes. Still the mechanism(s) by which polyglutamine proteins are ubiquitinated and degraded remains obscure. Here, for the first time, we demonstrate that Mahogunin 21 ring finger 1 E3 ubiquitin protein ligase is depleted in cells that express expanded-polyglutamine proteins. MGRN1 co-immunoprecipitates with expanded-polyglutamine huntingtin and ataxin-3 proteins. Furthermore, we show that MGRN1 is predominantly colocalized and recruits with polyglutamine aggregates in both cellular and transgenic mouse models. Finally, we demonstrate that the partial depletion of MGRN1 increases the rate of aggregate formation and cell death, whereas the overexpression of MGRN1 reduces the frequency of aggregate formation and provides cytoprotection against polyglutamine-induced proteotoxicity. These observations suggest that stimulating the activity of MGRN1 ubiquitin ligase might be a potential therapeutic target to eliminate the cytotoxic threat in polyglutamine diseases.
Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India.
Deepak
D
Chhangani
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
Nobuyuki
N
Nukina
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Masaru
M
Kurosawa
Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India.
Ayeman
A
Amanullah
Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India.
Vibhuti
V
Joshi
Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India.
Arun
A
Upadhyay
Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India. Electronic address: amit@iitj.ac.in.
Amit
A
Mishra
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D006801:Humans; D000071058:Huntingtin Protein; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
C086055:HTT protein, human; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D010455:Peptides; D012333:RNA, Messenger; D025801:Ubiquitin; C097188:polyglutamine; C470690:MGRN1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
Aggregation; Cytotoxicity; MGRN1; Polyglutamine disease