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Systemic deregulation of autophagy upon loss of ALS- and FTD-linked C9orf72

Yon Ju Ji1,2, Janet Ugolino1,2, Nathan Ryan Brady3

  • 1a Department of Biochemistry and Molecular Biology , Bloomberg School of Public Health, Johns Hopkins University , Baltimore , MD USA.

Autophagy
|March 21, 2017
PubMed

Insights

The C9orf72 gene mutation is linked to ALS and FTD. Loss of C9orf72 protein disrupts autophagy regulation, impacting cell function and neurodegeneration.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • C9orf72 gene mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  • The function of the C9orf72 protein, reduced in ALS and FTD, is not well understood.
  • Understanding C9orf72's role is crucial for neurodegenerative disease research.

Purpose of the Study:

  • To investigate the function of the C9orf72 protein.
  • To explore the role of C9orf72 in regulating autophagy.
  • To determine the implications of C9orf72 dysfunction in neurodegeneration.

Main Methods:

  • Utilized a C9orf72 knockout mouse model.
  • Performed cellular analyses to examine autophagy regulators.
  • Investigated the interaction between C9orf72 and SMCR8.

Main Results:

  • Loss of C9orf72 alters central autophagy signaling regulators.
  • C9orf72 depletion reduces MTOR activity and increases TFEB nuclear translocation.
  • Cells lacking C9orf72 show enlarged lysosomes and enhanced autophagic flux.
  • Loss of SMCR8, a C9orf72 partner, causes similar cellular phenotypes.

Conclusions:

  • C9orf72 acts as a negative regulator of autophagy.
  • C9orf72 links cellular metabolism to autophagy regulation.
  • C9orf72 is a key component of autophagy signaling with implications for neurodegeneration.
Keywords:
ALSC9orf72FTDMTORSMCR8TFEBautophagylysosomeneurodegenerationp62

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