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TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport

Hongyi Wu1, Loo Chien Wang2, Belle M Sow1

  • 1Mechanobiology Institute, National University of Singapore (NUS), Singapore, Singapore.

Nature Communications
|October 18, 2024
PubMed

Insights

Protein aggregation in human cells forms diverse inclusions. A key protein, TDP43, aggregates at ER exit sites in Amyotrophic Lateral Sclerosis (ALS), disrupting cellular transport.

Area of Science:

  • Cellular Biology
  • Neuroscience
  • Protein Biochemistry

Background:

  • Protein aggregation is central to age-related diseases.
  • Mechanisms of protein aggregate formation and their cellular impact are not fully understood.
  • Identifying proteins forming aggregates under proteotoxic stress is crucial.

Purpose of the Study:

  • To identify proteins forming aggregates in human cells under proteotoxic stress.
  • To characterize the distinct types of protein inclusions formed.
  • To investigate the role of TDP43 aggregation in Amyotrophic Lateral Sclerosis (ALS).

Main Methods:

  • Utilized a reporter system based on mutant Hsp104 to detect protein aggregates.
  • Analyzed protein aggregation in human cells subjected to proteotoxic stress.
  • Examined the localization and dynamics of TDP43 within different aggregate types.
  • Investigated the impact of TDP43 aggregation on ER-to-Golgi transport.

Main Results:

  • Over 300 proteins were identified forming distinct aggregate inclusions.
  • TDP43 dynamically partitioned between stress granules and novel non-dynamic inclusions at ER exit sites (ERES).
  • TDP43-ERES co-aggregation was induced by various proteotoxic stresses and observed in ALS patient motor neurons.
  • TDP43 aggregation at ERES caused cargo retention, delaying ER-to-Golgi transport.

Conclusions:

  • Proteotoxic stress induces diverse protein aggregation pathways.
  • TDP43 aggregation at ERES represents a novel pathogenic mechanism in ALS.
  • Disruption of ER-to-Golgi transport due to TDP43 aggregation contributes to cellular dysfunction in ALS.

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