Aggregation of Huntingtin in Neuronal Intranuclear Inclusions and Dystrophic Neurites in Brain
Science · 1997 · 2.9K citations · 30 references
The cause of neurodegeneration in Huntington’s disease is unknown, though patients possess an expanded N‑terminal polyglutamine region in huntingtin. A mutant huntingtin N‑terminal fragment accumulates in neuronal intranuclear inclusions and dystrophic neurites in HD cortex and striatum, with polyglutamine length affecting accumulation; ubiquitin co‑localizes, indicating proteolytic targeting yet resistance, implying aggregation may drive disease.
The cause of neurodegeneration in Huntington's disease (HD) is unknown. Patients with HD have an expanded NH 2 -terminal polyglutamine region in huntingtin. An NH 2 -terminal fragment of mutant huntingtin was localized to neuronal intranuclear inclusions (NIIs) and dystrophic neurites (DNs) in the HD cortex and striatum, which are affected in HD, and polyglutamine length influenced the extent of huntingtin accumulation in these structures. Ubiquitin was also found in NIIs and DNs, which suggests that abnormal huntingtin is targeted for proteolysis but is resistant to removal. The aggregation of mutant huntingtin may be part of the pathogenic mechanism in HD.
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