Huntington's disease (HD) is an autosomal dominant, late-onset neurodegenerative disorder characterized by a selective neuronal cell death in cortex and striatum leading to cognitive dysfunction, motor impairment, and personality changes. The underlying cause of HD is the expansion of a CAG repeat that is located within the first exon of the huntingtin gene (htt).
The current hypothesis in HD is that neuronal degeneration results from the combined effects of a gain of function in the mutated form of htt along with a loss of function in the wild-type htt.
Pathogenesis in HD appears to involve different mechanisms.
1. HD mutation is translated into an expanded polyglutamine tract (polyQ) that induces conformational changes and abnormal folding in the mutated htt. In order to protect itself, the cell accumulated these insoluble proteins into ubiquitinated cytoplasmic perinuclear aggregates. These perinuclear inclusions can impair the ubiquitin-proteasome system, leading to the accumulation of more misfolded proteins and cell death.
2. HD mutation results in abnormal protein interactions. Mutant htt interferes with the binding of PSD-95 to NMDA receptor, which allows increased Ca2+ influx, leading to excitotoxicity. Additionally, increased Ca2+ levels activates caspases leading to cell apoptosis and cleavage of mutant htt generating toxic N-terminal fragments. In HD, mutant htt fails to bind to the repressor REST in the cytoplasm, resulting in more repressor in the nucleus and inhibition of the transcription of BDNF, which is an important survival factor for the striatal neurons. Decreased binding between mutant htt and proteins such as MLK2, HIP1, HIP14 leads to apoptotic cell death, impaired vesicle trafficking and endocytosis.
3. HD mutation leads to aggregate sequestration of various proteins, including transcription factors. Proteolytically cleaved N-terminal fragments of mutated htt can translocate into the nucleus to form neuronal intranuclear inclusions, which recruit transcription factors such as CBP, TBP and Sin3A and therefore disrupt gene transcription, leading to neurodegeneration.