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Mitochondrial Abnormalities and Synaptic Damage in Huntington's Disease: a Focus on Defective Mitophagy and

Neha Sawant1, Hallie Morton1, Sudhir Kshirsagar1

  • 1Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.

Molecular Neurobiology
|September 14, 2021
PubMed

Insights

Huntington's disease (HD) involves genetic mutations leading to neuron loss. Research shows abnormal mitochondria and impaired removal of damaged mitochondria contribute to HD progression, suggesting new therapeutic targets.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Huntington's disease (HD) is a fatal genetic disorder characterized by progressive loss of medium spiny neurons (MSN).
  • It stems from expanded polyglutamine repeats in the HD gene, causing symptoms like chorea, cognitive decline, and emotional disturbances.
  • Cellular dysfunctions implicated in HD include defective axonal transport, altered bioenergetics, and synaptic damage.

Purpose of the Study:

  • To review recent research on Huntington's disease progression.
  • To discuss advancements in cell and mouse models for HD.
  • To explore cellular changes, mitochondrial abnormalities, DNA damage, bioenergetics, oxidative stress, mitophagy, and therapeutic strategies.

Main Methods:

  • Review of recent scientific literature on Huntington's disease.
  • Analysis of cellular and molecular mechanisms underlying HD.
  • Examination of findings from cell and mouse models of HD.

Main Results:

  • Mutant huntingtin (mHtt) interacts with dynamin-related protein 1 (DRP1), causing excessive mitochondrial fragmentation and impaired axonal transport.
  • Failure to remove damaged mitochondria is an early event in HD progression.
  • Abnormal protein interactions and impaired synaptic mitophagy are key pathological features.

Conclusions:

  • Mitochondrial dynamics and mitophagy are critical in Huntington's disease pathogenesis.
  • Targeting mHtt-DRP1 interactions and enhancing synaptic mitophagy offer promising therapeutic avenues for HD.
  • Further research into these cellular mechanisms is crucial for developing effective treatments.

Keywords:
Huntington’s diseaseMitochondria-targeted therapiesMitochondrial abnormalitiesMitophagyMutant huntingtinPolyglutamine repeat expansion

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