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A role for mitochondria-ER crosstalk in amyotrophic lateral sclerosis 8 pathogenesis

Cathal Wilson1,2, Laura Giaquinto3,2, Michele Santoro3

  • 1Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Italy cathalwilson636@gmail.com.

Life Science Alliance
|January 27, 2025
PubMed

Insights

Amyotrophic lateral sclerosis (ALS) protein aggregates form due to mitochondrial damage influencing VAPB mutations. Reducing ER-mitochondrial contacts can attenuate this, offering a potential therapeutic target for ALS.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Protein aggregates in motoneurons are a hallmark of amyotrophic lateral sclerosis (ALS).
  • ALS8 is linked to VAPB mutations, affecting endoplasmic reticulum (ER) and organelle contacts.
  • The connection between protein aggregation and cellular dysfunction in ALS remains unclear.

Purpose of the Study:

  • To investigate the role of VAPB mutations in protein aggregation and cellular dysfunction in ALS.
  • To explore the link between ER-mitochondrial contacts and aggregate formation.
  • To identify potential therapeutic strategies by modulating these cellular processes.

Main Methods:

  • Developed a yeast model expressing human mutant and wild-type (WT) VAPB.
  • Analyzed inclusion formation and its link to mitochondrial damage.
  • Investigated the effect of reducing ER-mitochondrial contacts.
  • Validated findings in mammalian motoneuron cells.

Main Results:

  • Inclusion formation is developmentally regulated and linked to mitochondrial damage.
  • Reducing ER-mitochondrial contacts attenuated aggregate formation.
  • Co-expression of WT VAPB slowed mutant protein aggregation.
  • Results were confirmed in mammalian motoneuron models.

Conclusions:

  • Mitochondrial damage influences mutant VAPB aggregation via ER-mitochondrial contacts in ALS.
  • This process initiates a cascade leading to disease progression.
  • Modulating ER-mitochondrial contacts may offer a therapeutic avenue for ALS.

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