Wennagel Doris, Braz Barbara Yael, Capizzi Mariacristina, Barnat Monia, Humbert Sandrine
University Grenoble Alpes, Inserm, U1216, Grenoble Institute Neurosciences, Bâtiment Edmond J. Safra, Chemin Fortuné Ferrini, 38000 Grenoble, La Tronche, France.
University Grenoble Alpes, Inserm, U1216, Grenoble Institute Neurosciences, Bâtiment Edmond J. Safra, Chemin Fortuné Ferrini, 38000 Grenoble, La Tronche, France; Institut du Cerveau-Paris Brain Institute (ICM), Sorbonne Université, Inserm, CNRS, Hôpital Pitié-Salpêtrière, Paris, France.
Cell Rep. 2022 Aug 30;40(9):111261. doi: 10.1016/j.celrep.2022.111261.
Compelling evidence indicates that in Huntington's disease (HD), mutation of huntingtin (HTT) alters several aspects of early brain development such as synaptogenesis. It is not clear to what extent the partial loss of wild-type HTT function contributes to these abnormalities. Here we investigate the function of HTT in the formation of spines. Although larger spines normally correlate with more synaptic activity, cell-autonomous depletion of HTT leads to enlarged spines but reduced excitatory synaptic function. We find that HTT is required for the proper turnover of endogenous actin and to recruit AMPA receptors at active synapses; loss of HTT leads to LIM kinase (LIMK) hyperactivation, which maintains cofilin in its inactive state. HTT therefore influences actin dynamics through the LIMK-cofilin pathway. Loss of HTT uncouples spine structure from synaptic function, which may contribute to the ultimate development of HD symptoms.
有力证据表明，在亨廷顿舞蹈症（HD）中，亨廷顿蛋白（HTT）的突变会改变早期大脑发育的多个方面，如突触形成。目前尚不清楚野生型HTT功能的部分丧失在多大程度上导致了这些异常。在这里，我们研究了HTT在棘突形成中的功能。虽然较大的棘突通常与更多的突触活动相关，但HTT的细胞自主缺失会导致棘突增大，但兴奋性突触功能降低。我们发现，HTT是内源性肌动蛋白正常周转以及在活跃突触处募集AMPA受体所必需的；HTT的缺失会导致LIM激酶（LIMK）过度激活，从而使丝切蛋白维持在非活性状态。因此，HTT通过LIMK-丝切蛋白途径影响肌动蛋白动力学。HTT的缺失使棘突结构与突触功能解偶联，这可能导致HD症状的最终发展。
