Autophagy is a mechanism responsible for the degradation of cellular components to maintain their homeostasis. However, autophagy is commonly altered and compromised in several diseases, including neurodegenerative disorders. Parkinson’s disease (PD) can be considered a multifactorial disease because environmental factors, genetic factors, and aging are involved. Several genes are involved in PD pathology, among which the LRRK2 gene and its mutations, inherited in an autosomal dominant manner, are responsible for most genetic PD cases. The R1441G LRRK2 mutation is, after G2019S, the most important in PD pathogenesis. Our results demonstrate a relationship between the R1441G LRRK2 mutation and a mechanistic dysregulation of autophagy that compromises cell viability. This altered autophagy mechanism is associated with organellar stress including mitochondrial (which induces mitophagy) and endoplasmic reticulum (ER) stress, consistent with the fact that patients with this mutation are more vulnerable to toxins related to PD, such as MPP⁺.

Graphical abstract

中文翻译：

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帕金森病 LRRK2 R1441G 突变显示巨自噬-线粒体自噬失调伴随内质网应激

自噬是一种负责降解细胞成分以维持其体内平衡的机制。然而，自噬在包括神经退行性疾病在内的几种疾病中通常会发生改变和损害。帕金森病 (PD) 可以被认为是一种多因素疾病，因为涉及环境因素、遗传因素和衰老。PD 病理学涉及多个基因，其中以常染色体显性遗传方式遗传的LRRK2基因及其突变是大多数遗传性 PD 病例的原因。R1441G LRRK2突变是继 G2019S 之后在 PD 发病机制中最重要的突变。我们的结果证明了 R1441G LRRK2之间的关系突变和损害细胞活力的自噬机制失调。这种改变的自噬机制与细胞器应激相关，包括线粒体（诱导线粒体自噬）和内质网（ER）应激，这与具有这种突变的患者更容易受到与 PD 相关的毒素（如 MPP ⁺ ）的影响这一事实一致。

图形概要