Молекулярная биология, 2022, T. 56, № 2, стр. 181-205

Прогерин и его роль в ускоренном и естественном старении

М. И. Мосевицкий ab*

a Петербургский институт ядерной физики им. Б.П. Константинова, Курчатовский научный центр
188300 Гатчина, Россия

b Институт высокомолекулярных соединений Российской академии наук
199004 Санкт-Петербург, Россия

* E-mail: m_mosev@mail.ru

Поступила в редакцию 18.02.2021
После доработки 21.06.2021
Принята к публикации 21.06.2021

Аннотация

Известные теории старения базируются на определенном метаболическом изъяне, негативно влияющем на жизнедеятельность клетки, будь то окислительный стресс, накопление дефектов в ДНК, исчерпание теломер, нарушения эпигенетических процессов. С позиций рассматриваемой в настоящем обзоре теории старения в основе всех этих нарушений лежит накопление на внутренней стороне ядерной оболочки белка прогерина – дефектного предшественника белка ядерного матрикса ламина А, сохранившего подлежащий удалению С-концевой остаток цистеина с присоединенной гидрофобной олигоизопреновой цепочкой. С помощью этой цепочки молекулы прогерина прикрепляются к внутренней мембране оболочки ядра, оттесняя примыкавшие к ней фибриллы ядерного матрикса и периферию хроматина. При этом изменяются морфология и форма ядра, нарушаются свойства его оболочки и вмонтированных в нее поровых комплексов. По мере накопления прогерина структурные искажения в ядре нарастают, вызывая все большие нарушения ядерно-цитоплазматического транспорта макромолекул, что ведет к нарушению клеточного метаболизма. Это приводит к нарастающей со временем гибели клеток и старению организма. Такой механизм старения приводит к развитию синдрома ускоренного старения (прогерии) Хатчинсона–Гилфорда (Hutchinson–Gilford progeria syndrome). Повышенная продукция прогерина при этой болезни связана с точечной мутацией c.1824C→T в экзоне 11 гена LMNA, кодирующего ламины А и С. Эта мутация стимулирует нестандартный сплайсинг первичного транскрипта при формировании мРНК предшественника ламина А, в результате чего образуется прогерин. Больные прогерией дети, получившие от одного из родителей указанную мутацию, быстро стареют и умирают в возрасте до 15 лет. Лечение прогерии направлено на предотвращение образования прогерина или уничтожение уже накопленного прогерина. В последнем случае перспективно применение рапамицина и его аналогов, а также других веществ, активирующих систему аутофагии, способную очищать клетку от прогерина. Обнаружение прогерина, хотя и в значительно меньшем количестве, у людей, не страдающих прогерией, указывает на участие этого белка и в “естественном” старении. Максимальный возраст, до которого может дожить человек, можно вычислить, если учитывать роль прогерина в сокращении теломер. Обнадеживающие предварительные результаты по очистке клеток от прогерина позволяют разработать оптимальную процедуру периодической очистки организма человека от прогерина, применение которой снизит темп старения.

Ключевые слова: прогерин, ядерно-цитоплазматический транспорт, клеточный метаболизм, ускоренное старение, естественное старение, максимальный возраст, активация аутофагии, активация теломеразы

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