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Evaluating Cell Death Signaling by Immunofluorescence in a Rat Model of Ischemic Stroke
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Evaluating Cell Death Signaling by Immunofluorescence in a Rat Model of Ischemic Stroke

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Mitochondria-associated endoplasmic reticulum membranes tethering protein VAPB-PTPIP51 protects against ischemic

Mingyang Li1, Yonggang Zhang1, Guixiang Yu2

  • 1Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.

CNS Neuroscience & Therapeutics
|April 8, 2024
PubMed
Abstract

Insights

Downregulation of VAPB-PTPIP51 compromises mitochondria-associated endoplasmic reticulum membranes (MAMs) in ischemic stroke. This exacerbates brain injury by inhibiting the PI3K pathway and activating autophagy, suggesting new therapeutic targets.

Area of Science:

  • Cellular Biology
  • Neuroscience
  • Pathology

Background:

  • Mitochondria-associated endoplasmic reticulum membranes (MAMs) are critical for cellular function, linking the endoplasmic reticulum (ER) and mitochondria.
  • Vesicle-associated membrane protein-associated protein B (VAPB) and protein tyrosine phosphatase interacting protein 51 (PTPIP51) are key proteins in MAMs formation and stability.
  • The role of MAMs in ischemic stroke (IS) pathogenesis is not well understood.

Purpose of the Study:

  • To investigate the role of the MAMs tethering proteins VAPB-PTPIP51 in experimental cerebral ischemia.
  • To understand how VAPB-PTPIP51 affects brain injury and cellular pathways in ischemic stroke.

Main Methods:

  • A mouse model of middle cerebral artery occlusion (MCAO) was used to simulate cerebral ischemia-reperfusion injury (CIRI).
  • Transmission electron microscopy (TEM) was employed to assess mitochondria-ER contact (MERC) coverage and distance.
  • VAPB or PTPIP51 knockdown was performed, and the PI3K/AKT/mTOR pathway was analyzed. PI3K activator treatment was also evaluated.

Main Results:

  • A decrease in VAPB-PTPIP51 expression was observed in brain tissue after MCAO.
  • MCAO led to compromised MAMs, characterized by reduced MERC coverage and increased distance.
  • VAPB or PTPIP51 knockdown exacerbated MAMs damage, increasing autophagy, reactive oxygen species (ROS), infarct area, and neurological deficits.
  • Inhibition of the PI3K/AKT/mTOR pathway was observed, and PI3K activator treatment mitigated the damage.

Conclusions:

  • Downregulation of VAPB-PTPIP51 in ischemic stroke causes structural damage to MAMs.
  • This damage exacerbates cerebral ischemia-reperfusion injury by inhibiting the PI3K pathway and activating autophagy.
  • VAPB-PTPIP51 and its associated pathways represent potential therapeutic targets for ischemic stroke.
Keywords:
MAMsPI3K/AKT/mTORVAPB‐PTPIP51autophagyischemic stroke

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