Reduced Expression of Foxp1 as a Contributing Factor in Huntington's Disease

Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine expansion in the huntington protein (het). The neuropathological hallmark of HD is the loss of neurons in the striatum and, to a lesser extent, in the cortex. Foxp1 is a member of the Forkhead family of transcription factors expressed selectively in the striatum and the cortex. In the brain, three major Foxp1 isoforms are expressed: isoform-A (similar to 90 kDa), isoform-D (similar to 70 kDa), and isoform-C (similar to 50 kDa). We find that expression of Foxp1 isoform-A and -D is selectively reduced in the striatum and cortex of R6/2 HD mice as well as in the striatum of HD patients. Furthermore, expression of mutant htt in neurons results in the downregulation of Foxp1. Elevating expression of isoform-A or -D protects cortical neurons from death caused by the expression of mutant hit. On the other hand, knockdown of Foxp1 promotes death in otherwise healthy neurons. Neuroprotection by Foxp1 is likely to be mediated by the transcriptional stimulation of the cell-cycle inhibitory protein p21^{Waf1/Cip1}. Consistently, Foxp1 activates transcription of the p21^{Waf1/Cip1} gene promoter, and overexpression of Foxp1 in neurons results in the elevation of p21 expression. Moreover, knocking down of p21^{Waf1/Cip1} blocks the ability of Foxp1 to protect neurons from mut-Htt-induced neurotoxicity. We propose that the selective vulnerability of neurons of the striatum and cortex in HD is related to the loss of expression of Foxp1, a protein that is highly expressed in these neurons and required for their survival.