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Inappropriate Intrusion of an Axonal Mitochondrial Anchor into Dendrites Causes Neurodegeneration

Dinesh C Joshi1, Chuan-Li Zhang1, Lavanya Babujee2

  • 1Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.

Cell Reports
|October 17, 2019
PubMed

Insights

Syntaphilin (SNPH) anchors mitochondria to axons. In a multiple sclerosis model, SNPH wrongly enters dendrites, causing neurodegeneration. Blocking this SNPH intrusion may be a therapeutic strategy.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Mitochondrial Dynamics

Background:

  • Syntaphilin (SNPH) is a key protein anchoring mitochondria to axons.
  • Its normal exclusion from dendrites is crucial for neuronal health.
  • Dysregulation of SNPH localization is implicated in neurodegenerative conditions.

Purpose of the Study:

  • To investigate the role of SNPH spatial distribution in neurodegeneration.
  • To examine the consequences of aberrant SNPH dendritic localization in a mouse model of multiple sclerosis (MS).
  • To explore SNPH's impact on neuronal excitotoxicity and mitochondrial function.

Main Methods:

  • Utilized the Shiverer (Shi) mouse model, a model for progressive MS.
  • Employed viral transduction to reconstitute SNPH dendritic intrusion in SNPH-knockout (KO) mice.
  • Performed in vitro studies involving N-methyl-D-aspartate (NMDA) excitotoxicity assays.
  • Assessed mitochondrial calcium uptake and somal mitophagy.

Main Results:

  • Shiverer mice exhibit loss of SNPH spatial specificity, with SNPH inappropriately entering dendrites of cerebellar Purkinje cells.
  • Reintroducing dendritic SNPH in SNPH-KO mice sensitizes Purkinje cells to excitotoxicity upon climbing fiber stimulation.
  • In vitro, SNPH overexpression in dendrites impairs neuronal viability by inducing NMDA excitotoxicity, reducing mitochondrial calcium uptake, and blocking mitophagy.

Conclusions:

  • Inappropriate SNPH immobilization of dendritic mitochondria contributes to excitotoxicity and neurodegeneration.
  • Interfering with dendritic SNPH intrusion presents a potential therapeutic avenue for combating neurodegenerative diseases.
Keywords:
excitotoxicitymitochondriamultiple sclerosisneurodegenerationsyntaphilin

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