ERKed by LRRK2: a cell biological perspective on hereditary and sporadic Parkinson's disease.
The leucine rich repeat kinase 2 (LRRK2/dardarin) is implicated in autosomal dominant familial and sporadic Parkinson's disease (PD); mutations in LRRK2 account for up to 40% of PD cases in some populations. LRRK2 is a large protein with a kinase domain, a GTPase domain, and multiple potential protein interaction domains. As such, delineating the functional pathways for LRRK2 and mechanisms by which PD-linked variants contribute to age-related neurodegeneration could result in pharmaceutically tractable therapies. A growing number of recent studies implicate dysregulation of mitogen activated protein kinases 3 and 1 (also known as ERK1/2) as possible downstream mediators of mutant LRRK2 effects. As these master regulators of growth, differentiation, neuronal plasticity and cell survival have also been implicated in other PD models, a set of common cell biological pathways may contribute to neuronal susceptibility in PD. Here, we review the literature on several major cellular pathways impacted by LRRK2 mutations--autophagy, microtubule/cytoskeletal dynamics, and protein synthesis--in context of potential signaling crosstalk involving the ERK1/2 and Wnt signaling pathways. Emerging implications for calcium homeostasis, mitochondrial biology and synaptic dysregulation are discussed in relation to LRRK2 interactions with other PD gene products. It has been shown that substantia nigra neurons in human PD and Lewy body dementia patients exhibit cytoplasmic accumulations of ERK1/2 in mitochondria, autophagosomes and bundles of intracellular fibrils. Both experimental and human tissue data implicate pathogenic changes in ERK1/2 signaling in sporadic, toxin-based and mutant LRRK2 settings, suggesting engagement of common cell biological pathways by divergent PD etiologies.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Manish
M
Verma
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Erin K
EK
Steer
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: ctc4@pitt.edu.
Charleen T
CT
Chu
D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
Autophagy; Cytoskeleton; LRRK2; MAPK; Mitophagy; Parkinson disease