title: 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.
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707, USA.
authors.forename: Ravindran
authors.initials: R
authors.lastname: Kumaran
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707, USA cookson@mail.nih.gov.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
mesh_terms: D000818:Animals; D017776:Autonomic Pathways / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D053858:Metabolic Networks and Pathways; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; C497604:SNCA protein, human; D051844:alpha-Synuclein; D016875:tau Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases