Mutant huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease

• DOI: 10.1093/hmg/ddr475
• Publication Date: 2011-10-14T02:50:07Z
• Authors: U. P. Shirendeb; M. J. Calkins; M. Manczak; V. Anekonda; B. Dufour; J. L. McBride; P. Mao; P. H. Reddy
• Keywords: Huntingtin Protein; Axoplasmic transport

The purpose of this study was to investigate the link between mutant huntingtin (Htt) and neuronal damage in relation mitochondria Huntington's disease (HD). In an earlier study, we determined relationship Htt mitochondrial dynamics/synaptic viability HD patients. We found loss, abnormal dynamics association with current sought expand on our previous findings further elucidate synaptic deficiencies. hypothesized that Htt, mitochondria, alters dynamics, leading fragmentation defective axonal transport neurons. using postmortem brains primary neurons from transgenic BACHD mice, identified interaction protein Drp1 factors cause including GTPase enzymatic activity. Further, for first time, studied degeneration. also investigated effect aggregates oligomers deficiencies mice. interacts Drp1, elevates activity, increases results anterograde movement These observations support hypothesis provide data can be utilized develop therapeutic targets are capable inhibiting decreasing fragmentation, enhancing protecting synapses toxic insults caused by Htt.