Reduced expression of foxpl 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 (htt). The neuropathological hallmark of HDis 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 (~90 kDa), isoform-D (~70 kDa), and isoform-C (~50 kDa). We find that expression of Foxp1 isoform-A and -D is selectively reduced in the striatum and cortex of R6/2HDmice as well as in the striatum ofHDpatients. 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 htt. 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 over expression of Foxp1 in neurons results in the elevation of p21 expression. Moreover, knockingdownof 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.