Pathways to Parkinsonism Redux: convergent pathobiological mechanisms in genetics of Parkinson's disease

Abstract

In the past few years, there have been a large number of genes identified that contribute to the lifetime risk of Parkinson's disease (PD). Some genes follow a Mendelian inheritance pattern, but others are risk factors for apparently sporadic PD. Here, we will focus on those genes nominated by genome-wide association studies (GWAS) in sporadic PD, with a particular emphasis on genes that overlap between familial and sporadic disease such as those encoding a-synuclein (SNCA), tau (MAPT), and leucine-rich repeat kinase 2 (LRRK2). We will advance the view that there are likely relationships between these genes that map not only to neuronal processes, but also to neuroinflammation. We will particularly discuss evidence for a role of PD proteins in microglial activation and regulation of the autophagy-lysosome system that is dependent on microtubule transport in neurons. Thus, there are at least two non-mutually exclusive pathways that include both non-cell-autonomous and cell-autonomous mechanisms in the PD brain. Collectively, these data have highlighted the amount of progress made in understanding PD and suggest ways forward to further dissect this disorder.

Figure 1.

Schematic overview of frequency and conferred risk of genes and genetic loci associated with the development of familial and idiopathic PD/parkinsonism. Genes listed in the red circle represent those identified through analysis of familial cases and give rise to monogenic forms of PD. The green circle contains genes in loci nominated as risk factors for idiopathic PD following meta-analysis of all European GWAS data sets. Lastly, the orange circle highlights a number of high-risk variants with reported odds ratios of >5. Adapted from (131).

Figure 2.

Molecular processes involved in PD pathogenesis as highlighted by genetic findings. Using genes recently nominated as risk factors for idiopathic PD along with those responsible for familial PD, it is possible to extrapolate a number of cellular processes that may underlie disease development. Each large gray circle represents a biological process and details the genes linked to it. Genes listed in italics represent nominated risk factors for idiopathic PD, identified through GWAS, whereas those in normal font are associated with familial PD. An asterisk denotes that the gene is linked to both forms of the disorder. Some genes like SNCA and LRRK2 are associated with multiple processes. While the majority of cellular pathways contribute to both familial and sporadic forms of the disease, neuroinflammations likely plays a more prominent role the latter. Conversely, mitochondrial dysfunction shows a greater association with familial PD. Adapted from (132).