Laboratorio Nazionale CIB (LNCIB), Area Science Park, Padriciano 99, 34149 Trieste, Italy; Department of Life Sciences (DSV), University of Trieste, 34127 Trieste, Italy.
Laboratorio Nazionale CIB (LNCIB), Area Science Park, Padriciano 99, 34149 Trieste, Italy; Department of Life Sciences (DSV), University of Trieste, 34127 Trieste, Italy.
Cell Rep. 2021 Sep 14;36(11):109694. doi: 10.1016/j.celrep.2021.109694.
Chromatin organization plays a crucial role in tissue homeostasis. Heterochromatin relaxation and consequent unscheduled mobilization of transposable elements (TEs) are emerging as key contributors of aging and aging-related pathologies, including Alzheimer's disease (AD) and cancer. However, the mechanisms governing heterochromatin maintenance or its relaxation in pathological conditions remain poorly understood. Here we show that PIN1, the only phosphorylation-specific cis/trans prolyl isomerase, whose loss is associated with premature aging and AD, is essential to preserve heterochromatin. We demonstrate that this PIN1 function is conserved from Drosophila to humans and prevents TE mobilization-dependent neurodegeneration and cognitive defects. Mechanistically, PIN1 maintains nuclear type-B Lamin structure and anchoring function for heterochromatin protein 1α (HP1α). This mechanism prevents nuclear envelope alterations and heterochromatin relaxation under mechanical stress, which is a key contributor to aging-related pathologies.
染色质组织在组织稳态中起着至关重要的作用。异染色质松弛和随之而来的转座元件 (TEs) 的非计划性动员，正在成为衰老和与衰老相关的病理学（包括阿尔茨海默病 (AD) 和癌症）的关键贡献者。然而，在病理条件下控制异染色质维持或其松弛的机制仍知之甚少。在这里，我们表明 PIN1 是唯一的磷酸化特异性顺/反式脯氨酰异构酶，其缺失与早衰和 AD 有关，对于维持异染色质是必不可少的。我们证明，这种 PIN1 功能从果蝇到人类都是保守的，可以防止 TE 动员依赖性的神经退行性变和认知缺陷。在机制上，PIN1 维持核 B 型 lamin 结构和异染色质蛋白 1α (HP1α) 的锚定功能。这种机制防止了核膜改变和机械应激下异染色质松弛，这是与衰老相关的病理学的一个关键贡献者。
