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Mahogunin ring finger 1 confers cytoprotection against mutant SOD1 aggresomes and is defective in an ALS mouse model

Deepak Chhangani1, Fumito Endo2, Ayeman Amanullah1

  • 1Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India.

Neurobiology of Disease
|November 27, 2015
PubMed

Insights

Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase helps clear toxic mutant SOD1 aggregates in ALS models. Dysregulation of MGRN1 impairs this process, suggesting it

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Proteotoxicity from misfolded proteins, like mutant copper-zinc superoxide dismutase (SOD1), drives neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).
  • Cellular quality control (QC) mechanisms preventing mutant SOD1 aggregation are not fully understood.

Purpose of the Study:

  • To investigate the role of Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase in the cellular response to mutant SOD1 aggregation.
  • To identify MGRN1 as a potential therapeutic target for ALS and other neurodegenerative diseases.

Main Methods:

  • Examined MGRN1 expression and localization in cellular and mouse models of ALS.
  • Investigated MGRN1 interaction with mutant SOD1 forms.
  • Assessed the impact of MGRN1 overexpression on mutant SOD1 aggregation and proteotoxicity.
  • Analyzed MGRN1 co-localization with autophagy markers (p62, Lamp2) in motor neuron inclusions.

Main Results:

  • MGRN1 was dysregulated in ALS models and preferentially interacted with mutant SOD1.
  • Presymptomatic ALS mice showed reduced MGRN1 cytoplasmic distribution.
  • MGRN1 was recruited to mutant SOD1 inclusions, suggesting involvement in their clearance.
  • MGRN1 overexpression reduced mutant SOD1 aggregation and proteotoxicity.

Conclusions:

  • MGRN1 facilitates the clearance of toxic mutant SOD1 aggregates, likely via the autophagic pathway.
  • MGRN1 sequestration contributes to motor neuron degeneration in ALS models.
  • The MGRN1-mediated protein QC pathway represents a novel therapeutic target for neurodegenerative diseases.
Keywords:
Amyotrophic lateral sclerosisCytotoxicityMGRN1Protein aggregationSOD1

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