Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière; Institut National de la Santé et de la Recherche Médicale U.975, Paris, France.
Physiol Rev. 2011 Oct;91(4):1161-218. doi: 10.1152/physrev.00022.2010.
Parkinson's disease (PD) is a common motor disorder of mysterious etiology. It is due to the progressive degeneration of the dopaminergic neurons of the substantia nigra and is accompanied by the appearance of intraneuronal inclusions enriched in α-synuclein, the Lewy bodies. It is becoming increasingly clear that genetic factors contribute to its complex pathogenesis. Over the past decade, the genetic basis of rare PD forms with Mendelian inheritance, representing no more than 10% of the cases, has been investigated. More than 16 loci and 11 associated genes have been identified so far; genome-wide association studies have provided convincing evidence that polymorphic variants in these genes contribute to sporadic PD. The knowledge acquired of the functions of their protein products has revealed pathways of neurodegeneration that may be shared between inherited and sporadic PD. An impressive set of data in different model systems strongly suggest that mitochondrial dysfunction plays a central role in clinically similar, early-onset autosomal recessive PD forms caused by parkin and PINK1, and possibly DJ-1 gene mutations. In contrast, α-synuclein accumulation in Lewy bodies defines a spectrum of disorders ranging from typical late-onset PD to PD dementia and including sporadic and autosomal dominant PD forms due to mutations in SCNA and LRRK2. However, the pathological role of Lewy bodies remains uncertain, as they may or may not be present in PD forms with one and the same LRRK2 mutation. Impairment of autophagy-based protein/organelle degradation pathways is emerging as a possible unifying but still fragile pathogenic scenario in PD. Strengthening these discoveries and finding other convergence points by identifying new genes responsible for Mendelian forms of PD and exploring their functions and relationships are the main challenges of the next decade. It is also the way to follow to open new promising avenues of neuroprotective treatment for this devastating disorder.
帕金森病（PD）是一种常见的神秘病因运动障碍。它是由于黑质多巴胺能神经元的进行性退化，伴随着富含α-突触核蛋白的神经元内包涵体的出现，即路易体。越来越清楚的是，遗传因素有助于其复杂的发病机制。在过去的十年中，已经研究了具有孟德尔遗传的罕见 PD 形式的遗传基础，这些形式代表不超过 10%的病例。迄今为止，已经确定了 16 个以上的基因座和 11 个相关基因；全基因组关联研究提供了令人信服的证据，表明这些基因中的多态性变体有助于散发性 PD。对其蛋白质产物功能的了解揭示了可能在遗传性和散发性 PD 之间共享的神经退行性途径。在不同的模型系统中获得的令人印象深刻的数据集强烈表明，线粒体功能障碍在由 parkin 和 PINK1 引起的临床相似的早发性常染色体隐性 PD 形式中起着核心作用，并且可能与 DJ-1 基因突变有关。相比之下，路易体中的α-突触核蛋白积累定义了一个从典型的晚发性 PD 到 PD 痴呆的疾病谱，包括由于 SCNA 和 LRRK2 突变引起的散发性和常染色体显性 PD 形式。然而，Lewy 体的病理作用仍然不确定，因为它们可能存在于具有相同 LRRK2 突变的 PD 形式中，也可能不存在。自噬蛋白/细胞器降解途径的损伤正在成为 PD 中可能的统一但仍然脆弱的致病情况。通过鉴定负责孟德尔形式 PD 的新基因并探索其功能和关系，加强这些发现并找到其他趋同点，是未来十年的主要挑战。这也是为这种破坏性疾病寻找新的有希望的神经保护治疗方法的途径。
