Domenicale Chiara, Magnabosco Stefano, Morari Michele
Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy.
Neuronal Signal. 2023 Aug 16;7(3):NS20220040. doi: 10.1042/NS20220040. eCollection 2023 Sep.
Mutations in the leucine-rich repeat kinase 2 () gene are associated with familial and sporadic forms of Parkinson's disease (PD). Sporadic PD and LRRK2 PD share main clinical and neuropathological features, namely hypokinesia, degeneration of nigro-striatal dopamine neurons and α-synuclein aggregates in the form of Lewy bodies. Animals harboring the most common LRRK2 mutations, i.e. p.G2019S and p.R1441C/G, have been generated to replicate the parkinsonian phenotype and investigate the underlying pathogenic mechanisms. Disappointingly, however, LRRK2 rodents did not consistently phenocopy hypokinesia and nigro-striatal degeneration, or showed Lewy body-like aggregates. Instead, LRRK2 rodents manifested non-motor signs and dysregulated transmission at dopaminergic and non-dopaminergic synapses that are reminiscent of behavioral and functional network changes observed in the prodromal phase of the disease. LRRK2 rodents also manifested greater susceptibility to different parkinsonian toxins or stressors when subjected to dual-hit or multiple-hit protocols, confirming LRRK2 mutations as genetic risk factors. In conclusion, LRRK2 rodents represent a unique tool to identify the molecular mechanisms through which LRRK2 modulates the course and clinical presentations of PD and to study the interplay between genetic, intrinsic and environmental protective/risk factors in PD pathogenesis.
富含亮氨酸重复激酶2（LRRK2）基因的突变与家族性和散发性帕金森病（PD）相关。散发性PD和LRRK2相关的PD具有主要的临床和神经病理学特征，即运动迟缓、黑质纹状体多巴胺能神经元变性以及路易小体形式的α-突触核蛋白聚集。已培育出携带最常见LRRK2突变（即p.G2019S和p.R1441C/G）的动物，以复制帕金森病表型并研究潜在的致病机制。然而，令人失望的是，LRRK2啮齿动物并未始终如一地模拟运动迟缓及黑质纹状体变性，也未表现出路易小体样聚集。相反，LRRK2啮齿动物表现出非运动症状以及多巴胺能和非多巴胺能突触传递失调，这让人联想到在疾病前驱期观察到的行为和功能网络变化。当采用双重打击或多重打击方案时，LRRK2啮齿动物对不同的帕金森病毒素或应激源也表现出更高的易感性，证实LRRK2突变是遗传风险因素。总之，LRRK2啮齿动物是一种独特的工具，可用于确定LRRK2调节PD病程和临床表现的分子机制，并研究遗传、内在和环境保护/风险因素在PD发病机制中的相互作用。
