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因子 (TE) 的计划外动员正在成为衰老和衰老相关病理的关键因素，包括阿尔茨海默病 (AD) 和癌症。然而，在病理条件下控制异染色质维持或松弛的机制仍然知之甚少。在这里，我们展示了 PIN1，唯一的磷酸化特异性顺式/反式脯氨酰异构酶，其损失与过早衰老和 AD 相关，对于保存异染色质至关重要。我们证明了这种 PIN1 功能在果蝇中是保守的对人类并防止 TE 动员依赖性神经退行性变和认知缺陷。机制上，PIN1 维持核 B 型层粘连蛋白结构和异染色质蛋白 1α (HP1α) 的锚定功能。这种机制可防止机械应力下的核膜改变和异染色质松弛，这是与衰老相关的病理的关键因素。