Mitochondrial Abnormalities and Synaptic Damage in Huntington's Disease: a Focus on Defective Mitophagy and Mitochondria-Targeted Therapeutics.
Neha SawantHallie MortonSudhir KshirsagarArubala P ReddyP Hemachandra ReddyPublished in: Molecular neurobiology (2021)
Huntington's disease (HD) is a fatal and pure genetic disease with a progressive loss of medium spiny neurons (MSN). HD is caused by expanded polyglutamine repeats in the exon 1 of HD gene. Clinically, HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances. Several years of intense research revealed that multiple cellular changes, including defective axonal transport, protein-protein interactions, defective bioenergetics, calcium dyshomeostasis, NMDAR activation, synaptic damage, mitochondrial abnormalities, and selective loss of medium spiny neurons are implicated in HD. Recent research on mutant huntingtin (mHtt) and mitochondria has found that mHtt interacts with the mitochondrial division protein, dynamin-related protein 1 (DRP1), enhances GTPase DRP1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. Recent research also revealed that failure to remove dead and/or dying mitochondria is an early event in the disease progression. Currently, efforts are being made to reduce abnormal protein interactions and enhance synaptic mitophagy as therapeutic strategies for HD. The purpose of this article is to discuss recent research in HD progression. This article also discusses recent developments of cell and mouse models, cellular changes, mitochondrial abnormalities, DNA damage, bioenergetics, oxidative stress, mitophagy, and therapeutics strategies in HD.
Keyphrases
- oxidative stress
- dna damage
- cognitive decline
- cell death
- diabetic rats
- single cell
- ischemia reperfusion injury
- induced apoptosis
- reactive oxygen species
- endoplasmic reticulum
- spinal cord injury
- stem cells
- cell therapy
- prefrontal cortex
- multiple sclerosis
- dna repair
- early onset
- gene expression
- mild cognitive impairment
- protein protein
- amino acid
- nitric oxide
- endoplasmic reticulum stress
- body mass index
- bone marrow
- hydrogen peroxide