Молекулярный патогенез синдрома Дауна (трисомии 21)

Синдром Дауна обусловлен врожденной трисомией по хромосоме 21. Основу его патогенеза составляет ряд молекулярных цитопатических эффектов анеуплоидии, активно изучаемых в последнее время.

Цель: Анализ и изложение в виде нарративного обзора молекулярных механизмов негативного влияния на клетку трисомии по хромосоме 21. Первый из них – первичный дисбаланс экспрессии, обусловленный увеличением дозы генов хромосомы 21, и гиперфункция кодируемых ими ферментативных, транспортных, рецепторных, структурных и регуляторных белков. Помимо этого, наличие дополнительной хромосомы влечёт за собой вторичное глобальное нарушение экспрессии, которое обусловлено рядом цитопатических механизмов и приводит к формированию анеуплоидия-ассоциированного фенотипа. Среди данных механизмов рассматриваются проявления протеотоксичности (стехиометрический дисбаланс, перегруженность систем синтеза, фолдинга, посттрансляционных модификаций и деградации, торможение рибосомального биогенеза, активация программ интегрированного ответа на клеточный стресс), нарушение пространственной организации наследственного материала, нестабильность генома (в частности, хромосомная нестабильность), которая сопряжена с накоплением ошибок в разнообразных генах и активацией аутовоспаления.

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