Huntington's disease (HD) is one of a family of neurodegenerative diseases that are associated with the accumulation of aggregates of a mutant form of a protein bearing glutamine repeats, in this case the Huntingtin protein (Htt). It is still a matter of debate whether these aggregates are a cause or a consequence of neural loss. Another issue is whether neurodegeneration is caused by the function of mutant Htt or by loss of function of wild-type Htt—as there is evidence in favour of each hypothesis—or indeed by a combination of both.

Elena Catteneo and her collaborators have recently reported in Science 293, 493–497 (2001) that wild-type Htt enhances the survival of striatal neurons—those that degenerate in HD—by driving the expression of the brain-derived neurotrophic factor (BDNF) by neighbouring cortical neurons in the brain. This function is lost in neurons expressing mutant Htt. Furthermore, they found reduced levels of BDNF in aging model animals expressing mutant Htt—which show a selective loss of striatal neurons—compared with mice expressing wild-type Htt.

These new findings pave the way for therapeutic treatments for HD involving BDNF. However, it remains to be established how Htt regulates BDNF transcription and how the expression of mutant Htt leads to reduced BDNF levels. Interestingly, Htt aggregates have been reported to sequester CREB, a transcription factor that positively regulates BDNF expression (Nature Med. 7, 528–530; 2001), which provides a possible explanation. Taken together with the fact that wild-type Htt has been reported to protect neurons by interfering with the activation of caspases, an enzyme required for apoptotic cell death (J. Biol. Chem. 276, 14545–14548; 2001), whereas aggregates of mutant Htt might contribute to the activation of caspases (Neuron 3, 623–633; 1999), these data indicate that neurodegeneration is probably due to both a loss of the beneficial effects of Htt and the destructive effects of mutant Htt.