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

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.