Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium.
Neurobiol Dis. 2022 Oct 1;172:105806. doi: 10.1016/j.nbd.2022.105806. Epub 2022 Jun 30.
Parkinson's disease (PD) is currently considered a multisystemic disorder rather than a pure brain disease, in line with the multiple hit hypothesis from Braak. However, despite increasing evidence that the pathology might originate in the periphery, multiple unknown aspects and contradictory data on the pathological processes taking place in the periphery jeopardize the interpretation and therapeutic targeting of PD. Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been widely linked with familial and sporadic PD cases. However, the actual role of LRRK2 in PD pathophysiology is far from understood. There is evidence that LRRK2 may be involved in alpha-synuclein (α-synuclein) pathology and immune cell regulation, but it has also been associated with inflammatory diseases such as inflammatory bowel disease, tuberculosis, leprosy, and several other bacterial infections. In this review, we focus on the different roles of LRRK2 in the periphery. More specifically, we discuss the involvement of LRRK2 in the propagation of α-synuclein pathology and its regulatory role in peripheral inflammation. A deeper understanding of the multidimensional functions of LRRK2 will pave the way for more accurate characterization of PD pathophysiology and its association with other inflammatory diseases.
帕金森病（PD）目前被认为是一种多系统紊乱，而不是一种纯粹的脑部疾病，符合 Braak 的多次打击假说。然而，尽管有越来越多的证据表明病理学可能起源于外围，但关于发生在外周的病理过程的多个未知方面和矛盾数据，使得 PD 的解释和治疗靶向受到了威胁。富含亮氨酸重复激酶 2（LRRK2）基因突变已广泛与家族性和散发性 PD 病例相关。然而，LRRK2 在 PD 病理生理学中的实际作用还远未被理解。有证据表明，LRRK2 可能参与α-突触核蛋白（α-synuclein）病理学和免疫细胞调节，但它也与炎症性疾病有关，如炎症性肠病、结核病、麻风病和其他几种细菌感染。在这篇综述中，我们专注于 LRRK2 在周围组织中的不同作用。更具体地说，我们讨论了 LRRK2 在 α-synuclein 病理学传播中的作用及其在周围炎症中的调节作用。更深入地了解 LRRK2 的多维功能将为更准确地描述 PD 病理生理学及其与其他炎症性疾病的关联铺平道路。
