Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease

Abstract

Huntington's disease (HD) is a progressive, fatal neurodegenerative disease caused by expanded polyglutamine repeats in the HD gene. HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment and emotional disturbances. Research into mutant huntingtin (Htt) and mitochondria has found that mutant Htt interacts with the mitochondrial 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. This article summarizes latest developments in HD research and focuses on the role of abnormal mitochondrial dynamics and defective axonal transport in HD neurons. This article also discusses the therapeutic strategies that decrease mitochondrial fragmentation and neuronal damage in HD.

Figure 1

Schematic illustration of expanded polyQ repeats within exon 1 of Huntington’s disease gene.

Figure 2

Cellular changes that have been implicated in Huntington’s disease pathogenesis.

Figure 3

Schematic illustration showing mutant huntingtin interaction with mitochondrial protein, Drp1 and subsequent pathogenic changes in HD neuron.

Figure 4

Huntington’s disease neuron showing excessive fragmentation of mitochondria, accumulation in cell soma, and abnormal distribution of mitochondria in neuronal processes and synapses.

Figure 5

Possible therapeutic approaches for Huntington’s disease patients.