Терапевтический потенциал Hsp70 при БАС и других протеинопатиях: от молекулярных механизмов к генотерапии (обзор)
Актуальность: Нарушение клеточного протеостаза и агрегация патологических белков являются центральными звеньями патогенеза нейродегенеративных заболеваний, включая болезнь Альцгеймера, болезнь Паркинсона и боковой амиотрофический склероз. Существующие методы лечения в целом носят симптоматический характер, что создает острую потребность в стратегиях, направленных на восстановление гомеостаза белков. Цель исследования:Детально проанализировать нейропротекторный потенциал ключевого компонента шаперонной сети – белка теплового шока 70 кДа, уделяя особое внимание механизмам его действия при боковом амиотрофическом склерозе, в патогенезе которого центральное место занимает агрегация РНК-связывающих белков TDP-43 и FUS. Оценить возможности адресной доставки Hsp70 в ЦНС. Материалы и методы:В ходе подготовки обзора проведен анализ современных научных публикаций, посвященных изучению молекулярных механизмов шаперон-опосредованной нейропротекции, роли Hsp70 в регуляции протеостаза, а также существующим терапевтическим стратегиям – фармакологической индукции белка и применению экзогенного рекомбинантного белка – и ограничениям их клинического применения. Результаты:Рассмотрены три взаимосвязанных уровня нейропротекции, осуществляемой с помощью Hsp70: предотвращение первичной агрегации, в том числе за счет модуляции фазового разделения, ограниченный потенциал дезагрегации уже сформированных агрегатов («энтропийное вытягивание») и направление субстратов в системы убиквитин-протеасомной и аутофагальной деградации. Подчеркивается, что эффективность Hsp70 опосредована сложной сетью взаимодействий с Hsp90, различными ко-шаперонами, нуклеотид-обменными факторами и адаптерами (BAG3, CHIP). Проанализированы фундаментальные ограничения существующих подходов, связанные с доставкой и контекст-зависимой активностью Hsp70. Обоснована разработка генотерапевтических стратегий для лечения бокового амиотрофического склероза на основе аденоассоциированных вирусов, позволяющих обеспечить целевую, долговременную и контролируемую экспрессию Hsp70 в пораженных нейронах. Заключение:Обзор обобщает современные молекулярные данные о роли Hsp70 при нейродегенерации с анализом трансляционных перспектив, предлагая этот шаперон или его домены в качестве многофункционального средства при разработке болезнь-модифицирующей терапии БАС и некоторых других НДЗ
Броновицкий ЕВ, Чапров КД, Фуников СЮ, и др. Терапевтический потенциал Hsp70 при БАС и других протеинопатиях: от молекулярных механизмов к генотерапии (обзор). Научные результаты биомедицинских исследований. 2026;12(2):230-268. [Bronovitsky EV, Chaprov KD, Funikov SY, et al. Therapeutic potential of Hsp70 in ALS and other proteinopathies: from molecular mechanisms to gene therapy (review). Research Results in Biomedicine. 2026;12(2):230-268. Russian].
DOI: 10.18413/2658-6533-2026-12-2-0-4
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