Роль ретроэлементов в развитии болезни Паркинсона

Болезнь Паркинсона – второе по распространенности нейродегенеративное заболевание, характеризующееся накоплением альфа-синуклеина и телец Леви в черной субстанции головного мозга. Генетические исследования свидетельствуют об ассоциации с болезнью различных SNP, многие из которых расположены в межгенных и интронных областях, где локализованы также ретротранспозоны и произошедшие от них гены некодирующих РНК. В связи с этим сделано предположение о влиянии SNP в генах ретроэлементов на развитие болезни Паркинсона. Фактором предрасположенности является активация ретротранспозонов с возрастом, поскольку заболевание ассоциировано со старением. Предложена гипотеза о том, что альфа-синуклеин накапливается в головном мозге вследствие его взаимодействия с транскриптами активированных ретроэлементов. В результате дефектного противовирусного ответа и большого количества РНК-мишеней для данного белка его агрегаты образуют тельца Леви в нейронах с последующим воспалением черной субстанции и активацией нейродегенеративных процессов. В качестве доказательства приведены данные о роли альфа-синуклеина в противовирусном ответе со связыванием с РНК вирусов, которые характеризуются способностью активировать ретроэлементы, произошедшие в эволюции от встроенных в геном человека экзогенных вирусов. Обнаружены также активированные LINE1-ретроэлементы в головном мозге, эндогенные ретровирусы и LINE1 в сыворотке крови пациентов с болезнью Паркинсона. Дополнительный механизм, способствующий прогрессированию болезни, представляет собой дисфункция митохондрий вследствие инсерций в их геномы Alu-элементов с помощью ферментов LINE1. Описаны механизмы влияния активированных ретротранспозонов на произошедшие от них в эволюции микроРНК. Анализ научной литературы позволил выявить 35 таких микроРНК (miR-1246, -1249, -1271, -1273, -1303, -151, -211, -28, -31, -320b, -320d, -330, -335, -342, -374a, -374b, -421, -4293, -4317, -450b, -466, -487b, -493, -495, -5095, -520d, -576, -585, -6088, -619, -625, -626, -769, -885, -95), ассоциированных с болезнью Паркинсона, которые могут стать перспективными мишенями для ее лечения и диагностики.

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