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Visualization and Quantification of Endogenous Intra-Organelle Protein Interactions at ER-Mitochondria Contact Sites by Proximity Ligation Assays
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Visualization and Quantification of Endogenous Intra-Organelle Protein Interactions at ER-Mitochondria Contact Sites by Proximity Ligation Assays

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ALS/FTD-associated FUS activates GSK-3β to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations

Radu Stoica1, Sébastien Paillusson1, Patricia Gomez-Suaga1

  • 1Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.

EMBO Reports
|July 16, 2016
PubMed

Insights

Defective FUS protein disrupts connections between the endoplasmic reticulum and mitochondria, impairing cell function and potentially leading to amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). This disruption affects calcium signaling and ATP production, implicating GSK-3β in the disease process.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Defective FUS (fused in sarcoma) protein metabolism is linked to amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD).
  • Endoplasmic reticulum (ER) and mitochondria signaling, crucial for cellular functions disrupted in ALS/FTD, relies on physical organelle associations.
  • These associations are mediated by the VAPB-PTPIP51 scaffold, tethering ER and mitochondria.

Purpose of the Study:

  • To investigate the role of FUS in disrupting ER-mitochondria communication.
  • To understand the downstream effects of FUS-induced organelle uncoupling on cellular functions.
  • To explore the link between FUS, ER-mitochondria signaling, and ALS/FTD-associated kinases.

Main Methods:

  • Cellular models expressing FUS.
  • Assessment of VAPB-PTPIP51 interaction and ER-mitochondria contacts.
  • Measurement of mitochondrial calcium (Ca2+) uptake and ATP production.
  • Analysis of glycogen synthase kinase-3β (GSK-3β) activation.

Main Results:

  • FUS disrupts the VAPB-PTPIP51 interaction, reducing ER-mitochondria associations.
  • FUS expression impairs mitochondrial Ca2+ uptake and ATP production.
  • FUS-induced reduction in ER-mitochondria contacts correlates with GSK-3β activation.

Conclusions:

  • FUS directly interferes with the physical and functional links between ER and mitochondria.
  • Disruption of ER-mitochondria signaling by FUS contributes to cellular dysfunction relevant to ALS/FTD.
  • FUS-mediated alterations in organelle communication are linked to GSK-3β, a key kinase in ALS/FTD pathogenesis.
Keywords:
amyotrophic lateral sclerosisfrontotemporal dementiaglycogen synthase kinase‐3βprotein tyrosine phosphatase interacting protein 51vesicle‐associated membrane protein‐associated protein B

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