Update on pathogenesis and genetics

Abstract

Despite familial aggregation had long been recognized as a common feature in Parkinson Disease (PD), only in the past twenty years the contribution of genetics has been deeply explored, with the identification of few genes clearly responsible for mendelian forms of the disease, either with autosomal dominant (SNCA, LRRK2) or recessive (PARK2/Parkin, PINK1, DJ-1, ATP13A2) inheritance. Besides these, some other genes have been found mutated in rare families, and their actual contribution remains to be confirmed. Monogenic forms only explain a small minority of PD, leaving a large proportion of cases unaccounted. It is conceivable that in the vast majority of these patients, the disease underlies a multifactorial inheritance, with several common and rare genetic variants interplaying with epigenetic and with environmental factors to reach a threshold of disease. The most relevant example are heterozygous variants of the GBA gene, which represent a strong predisposing factor for PD development, with an average relative risk of about 5; moreover, several common variants (most residing within the same genes mutated in mendelian forms of PD) were identified as susceptibility factors by large whole genome association (GWA) studies. In line with this hypothesis, the advent of next generation sequencing (NGS) technologies, which have impressively enhanced the identification of novel causative genes in most genetic disorders, has not brought the expected revolution in the field of PD genetics. Indeed, only few rarely mutated genes have been found in isolated families, and whole exome sequencing efforts in large cohorts of PD patients have often failed to identify robust novel PD candidates. While it can be safely expected that the huge amount of genetic data generated through NGS and GWA strategies contains a wealth of new relevant information to better understand the complex genetic basis of PD, the meaningful analysis of such data to extrapolate novel PD candidate genes represents a truly challenging task. A possible lead to get oriented in the maze of common and rare genetic variants emerging from genome-wide studies may derive from the analysis of pathogenic mechanisms of neurodegeneration. Intriguingly, it is clearly emerging that neuronal death results as a consequence of the derangement of very few essential and highly interconnected cellular pathways, and that many if not all genetic factors implicated in PD pathogenesis converge on, and affect, the same cellular processes, including mitochondrial dysfunction, misfolded protein damage, impairment of clearance systems, abnormal calcium handling and enhanced pro-inflammatory responses.