Huntington's disease (HD) is an autosomal dominant, late-onset neurodegenerative disorder characterized by a selective neuronal cell death in the cortex and striatum leading to cognitive dysfunction, motor impairment, and behavioral changes. The underlying cause of HD is the expansion of a CAG repeat located within the first exon of the Huntingtin gene (HTT). In persons with HD, the HTT gene is found to contain 36 or more CAG repeats, resulting in a mutant form of the Huntingtin protein. 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.
HD mutation is translated into an expanded polyglutamine tract (polyQ) that induces conformational changes and abnormal folding in the mutated Huntingtin. These insoluble proteins accumulate as ubiquitinated cytoplasmic perinuclear aggregates. The resulting perinuclear inclusions impair the ubiquitinproteasome system, leading to the accumulation of more misfolded proteins and cell death.
HTT mutation results in abnormal protein interactions. For example, mutant Huntingtin interferes with the binding of disks large associated protein 4 (DLGAP4) to the glutamate receptor NMDAR1 (GRIN1). This results in receptor hypersensitivity, an influx of Ca2+, and excitotoxicity. Additionally, increased Ca2+ levels activate caspases leading to cell apoptosis, cleavage of mutant Huntingtin, and the generation of toxic N-terminal fragments. In HD, mutant Huntingtin can also inhibit transcription by failing to bind to the repressor REST in the cytoplasm. This results in an accumulation of the repressor in the nucleus and inhibition of brain-derived neurotrophic factor (BDNF) transcription, which is an important survival factor for striatal neurons. Finally, decreased binding between mutant Huntingtin and proteins such as MLK2 (MAP3K10), HIP1, and HIP14 leads to apoptotic cell death, impaired vesicle trafficking, and endocytosis.
Huntingtin mutation leads to aggregate sequestration of various proteins, including transcription factors. Proteolytically cleaved N-terminal fragments of mutated Huntingtin can translocate into the nucleus to form neuronal intranuclear inclusions. Once there, mutated Huntingtin recruits transcription factors such as CBP (CREBBP, EP300), TBP, and SIN3A which disrupt gene transcription leading to neurodegeneration.