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Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain

Shireen A Sarraf1, Hetal V Shah2, Gil Kanfer1

  • 1Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

Molecular Cell
|November 18, 2020
PubMed

Insights

The autophagy receptor TAX1BP1 is crucial for clearing toxic protein aggregates in neurons, protecting against neurodegenerative disease. Its absence leads to aggregate buildup and neuronal damage.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Molecular Biology

Background:

  • Protein aggregates disrupt cellular homeostasis and are linked to neurodegenerative diseases.
  • Selective autophagic elimination of aggregates is vital for protein quality control, but the targeting mechanisms remain unclear.

Purpose of the Study:

  • To investigate the role of autophagy receptor proteins, specifically TAX1BP1, in the clearance of proteotoxic aggregates.
  • To determine the therapeutic potential of TAX1BP1 in neurodegenerative diseases.

Main Methods:

  • Comparison of autophagy receptor requirements (OPTN, NBR1, p62, NDP52, TAX1BP1) for aggregate clearance.
  • Assessment of TAX1BP1's role in aggregate clearance in human induced pluripotent stem cell-derived neurons and TAX1BP1 knockout mouse models.
  • Analysis of protein aggregate levels, ubiquitin conjugates, and lipofuscin accumulation.

Main Results:

  • Endogenous TAX1BP1 is recruited to and essential for clearing stress-induced protein aggregates.
  • Ectopic TAX1BP1 expression enhances aggregate clearance via autophagy, improving neuronal viability.
  • TAX1BP1 depletion increases sensitivity to proteotoxicity, and its loss in vivo causes ubiquitin conjugate and lipofuscin accumulation in mouse brains.

Conclusions:

  • TAX1BP1 plays a critical role in the selective autophagic clearance of proteotoxic aggregates.
  • TAX1BP1 exhibits specific expression in the brain and mediates the clearance of diverse cytotoxic proteins.
  • TAX1BP1 represents a potential therapeutic target for neurodegenerative diseases characterized by protein aggregate accumulation.
Keywords:
Huntington’s diseaseOPTNaggregateaggrephagyautophagy receptorp62proteostasisproteotoxic stressselective autophagyubiquitin

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