Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine expansion in the huntington protein (). The neuropathological hallmark of HD is the loss of neurons in the striatum and, to a lesser extent, in the cortex.is a member of the Forkhead family of transcription factors expressed selectively in the striatum and the cortex. In the brain, three majorisoforms are expressed: isoform-A (∼90 kDa), isoform-D (∼70 kDa), and isoform-C (∼50 kDa). We find that expression ofisoform-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 mutantin neurons results in the downregulation ofElevating expression of isoform-A or -D protects cortical neurons from death caused by the expression of mutantOn the other hand, knockdown ofpromotes death in otherwise healthy neurons. Neuroprotection byis likely to be mediated by the transcriptional stimulation of the cell-cycle inhibitory proteinConsistently,activates transcription of thegene promoter, and overexpression ofin neurons results in the elevation of p21 expression. Moreover, knocking down ofblocks the ability ofto protect neurons from mut--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, a protein that is highly expressed in these neurons and required for their survival.Although the mutant huntingtin gene is expressed widely, neurons of the striatum and cortex are selectively affected in Huntington's disease (HD). Our results suggest that this selectivity is attributable to the reduced expression of Foxp1, a protein expressed selectively in striatal and cortical neurons that plays a neuroprotective role in these cells. We show that protection byinvolves stimulation of the() gene. Although three majorisoforms (A, C, and D) are expressed in the brain, only isoform-A has been studied in the nervous system. We show that isoform-D is also expressed selectively, neuroprotective and downregulated in HD mice and patients. Our results suggest thatmight be an attractive therapeutic target for HD.
Pubmed ID: 28550168 RIS Download
Mesh terms: Animals | Biomarkers | Cells, Cultured | Cerebral Cortex | Corpus Striatum | Down-Regulation | Female | Forkhead Transcription Factors | Humans | Huntingtin Protein | Huntington Disease | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Mice, Transgenic | Neurons | Repressor Proteins | Tissue Distribution
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