Departamento de Bioquímica Y Biología Molecular Y Genética, Facultad de Enfermería Y Terapia Ocupacional, Universidad de Extremadura, Cáceres, Spain.
Centro de Investigación Biomédica en Red de Enfermedades (CIBERNED), Madrid, Spain.
Cell Biol Toxicol. 2022 Oct;38(5):889-911. doi: 10.1007/s10565-021-09617-w. Epub 2021 May 31.
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.
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，自噬在几种疾病中经常发生改变和受损，包括神经退行性疾病。帕金森病（PD）可以被认为是一种多因素疾病，因为环境因素、遗传因素和衰老都与之相关。几个基因参与 PD 的病理过程，其中 LRRK2 基因及其突变以常染色体显性遗传方式遗传，是大多数遗传 PD 病例的原因。R1441G LRRK2 突变是继 G2019S 之后 PD 发病机制中最重要的突变。我们的结果表明，LRRK2 基因的 R1441G 突变与自噬的机制失调有关，这会损害细胞活力。这种改变的自噬机制与细胞器应激有关，包括线粒体（诱导自噬）和内质网（ER）应激，这与携带这种突变的患者更容易受到与 PD 相关的毒素（如 MPP）的影响的事实是一致的。
