Truncated N-terminal huntingtin fragment with expanded-polyglutamine （htt552-100Q） suppresses brain-derived neurotrophic factor transcription in astrocytes

Although huntingtin （htt） can be cleaved at many sites by caspases, calpains, and aspartyl proteases, amino acid （aa） 552 was defined as a preferred site for cleavage in human Huntington disease （HD） brains in vivo. To date, the normal function of wild-type N-terminal htt fragment 1-552 aa （htt552） and its pathological roles of mutant htt552 are still unknown. Although mutant htt （mhtt） is also expressed in astrocytes, whether and how mhtt con- tributes to the neurodegeneration through astrocytes in HD remains largely unknown. In this study, a glia HD model, using an adenoviral vector to express wild-type htt552 （htt552-18Q） and its mutation （htt552-100Q） in rat primary cortical astrocytes, was generated to investigate the influence of htt552 on the transcription of brain- derived neurotrophic factor （BDNF）. Results from enzyme linked immunosorbent assay showed that the level of BDNF in astrocyte-conditioned medium was decreased in the astrocytes expressing htt552-100Q. Quantitative real-time polymerase chain reaction demonstrated that htt552-100Q reduced the transcripts of the BDNF III and IV, hence, repressed the transcription of BDNF. Furthermore, immunofluorescence showed that aggre- gates formed by htt552-100Q entrapped transcription factors cAMP-response element-binding protein and stimulatory protein 1, which might account for the reduc- tion of BDNF transcription. These findings suggest that mhtt552 reduces BDNF transcription in astrocytes, which might contribute to the neuronal dysfunction in HD.