Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington's Disease

TLDR

Huntingtin, a 350‑kDa protein mutated in Huntington’s disease, is thought to exert a protective role in striatal neurons, and loss of this beneficial activity may contribute to neuronal death. The study proposes that restoring wild‑type huntingtin function and boosting BDNF production could serve as therapeutic strategies for Huntington’s disease. Wild‑type huntingtin up‑regulates transcription of brain‑derived neurotrophic factor (BDNF) in cortical neurons. Mutation of huntingtin abolishes its ability to up‑regulate BDNF, resulting in reduced cortical BDNF levels and consequent loss of neurotrophic support that leads to striatal neuron death.

Abstract

Huntingtin is a 350-kilodalton protein of unknown function that is mutated in Huntington's disease (HD), a neurodegenerative disorder. The mutant protein is presumed to acquire a toxic gain of function that is detrimental to striatal neurons in the brain. However, loss of a beneficial activity of wild-type huntingtin may also cause the death of striatal neurons. Here we demonstrate that wild-type huntingtin up-regulates transcription of brain-derived neurotrophic factor (BDNF), a pro-survival factor produced by cortical neurons that is necessary for survival of striatal neurons in the brain. We show that this beneficial activity of huntingtin is lost when the protein becomes mutated, resulting in decreased production of cortical BDNF. This leads to insufficient neurotrophic support for striatal neurons, which then die. Restoring wild-type huntingtin activity and increasing BDNF production may be therapeutic approaches for treating HD.