Механический стресс клеток мозга, локальная трансляция и нейродегенеративные заболевания: молекулярно-генетические аспекты

Идея о том, что хронический механический стресс, который испытывают клетки мозга при повышенном внутричерепном давлении, артериальной гипертензии или вследствие травмы, может быть одним из факторов риска в развитии нейродегенеративных заболеваний, появилась еще в 90-е годы прошлого столетия и поддерживается в настоящее время. Однако молекулярно-генетические механизмы реализации событий, ведущих от механического воздействия на клетки к нарушению пластичности синапсов и последующему изменению поведения, когнитивных способностей и памяти, не ясны. В настоящем обзоре рассмотрены существующие данные о молекулярно-генетических механизмах регуляции локальной трансляции и актинового цитоскелета в активированном синапсе, играющих центральную роль в формировании различных видов пластичности синапса и долговременной памяти, и возможных путях влияния механического стресса на их состояние. Обсуждается роль mTOR сигнального каскада, РНК-связывающего белка FMRP, белка CYFIP1, взаимодействующего с FMRP, семейства малых ГТФаз и WAVE регуляторного комплекса в регуляции инициации локальной трансляции и перестроек актинового цитоскелета в дендритных шипиках активированного синапса. Приводятся факты, свидетельствующие о том, что в условиях хронического механического стресса возможна аберрантная активация mTOR сигнального каскада и WAVE регуляторного комплекса через сенсор механических сигналов – регуляторный фактор YAP/TAZ, следствием которой могут быть нарушения активности системы локальной трансляции, а также связанных с ними механизмов регуляции формирования F-актиновых филаментов и структуры дендритных шипиков. Это может быть одной из причин развития различных неврологических патологий, включая аутистические расстройства и эпилептическую энцефалопатию. Высказывается оригинальная гипотеза, согласно которой одной из возможных причин синаптопатий может быть нарушение стабильности протеома, связанное с гиперактивностью mTOR и формированием сложных динамических режимов синтеза белков de novo в ответ на стимуляцию синапса, в том числе и в условиях хронического механического стресса.

синапс, механосенсор YAP/TAZ, mTOR, FMRP-зависимая трансляция, сложная динамика, F-актин, WAVE регуляторный комплекс, расстройства аутистического спектра, эпилептическая энцефалопатия

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