Huntington's disease and neurogenesis: FGF-2 to the rescue?

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by involuntary choreiform movements, cognitive impairment, metabolic abnormalities, and a relentlessly progressive course culminating in death 10–25 years after onset. Neuropathology studies of HD have established a stereotypical pattern of neurodegeneration and neuron loss, revealing that medium spiny neurons of the striatum are primarily affected followed by regions of the cerebral cortex (1). The genetic basis of HD is expansion of a CAG trinucleotide repeat within the huntingtin (htt) gene, resulting in the production of htt protein containing an expanded glutamine tract (2). Such “polyglutamine” tract expansions are now known to be the cause of nine inherited neurological diseases. As polyglutamine expansions misfold to produce altered peptide conformers that are resistant to the normal cellular processes of protein turnover, “aggregates” or “inclusions” of the aberrant protein accumulate within neurons in HD brain regions (3). The occurrence of mis-folded proteins that cannot be properly turned over is an emerging theme in neurodegenerative disease, as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, prion diseases, and polyglutamine repeat diseases such as HD all share this feature (4). Although much progress has been made in understanding the molecular genetic basis of HD, efforts to develop a cure or definitive treatment for HD have been complicated by an inadequate understanding of why certain populations of neurons degenerate within the striatum and cortex in HD despite widespread expression of the htt mutant protein throughout the central nervous system (CNS). Furthermore, polyglutamine-expanded htt can produce a myriad of nuclear and cellular abnormalities, accounting for the promulgation of a panorama of potential therapies directed at different aspects of the molecular pathology (5). One intriguing therapeutic option yet to be explored in HD is growth factor stimulation of endogenous neurogenesis. In this issue of PNAS, Jin et al. …