LRRK2 Pathways Leading to Neurodegeneration
- 1.7k Downloads
Mutations in LRRK2 are associated with inherited Parkinson’s disease (PD) in a large number of families, and the genetic locus containing the LRRK2 gene contains a risk factor for sporadic PD. The LRRK2 protein contains several domains that suggest a role in cellular signaling, including a kinase domain. It is also clear that LRRK2 interacts, either physically or genetically, with several other important proteins implicated in PD, suggesting that LRRK2 may be a central player in the pathways that underlie parkinsonism. As such, LRRK2 has been proposed to be a plausible target for therapeutic intervention, with kinase inhibition being pursued most actively. However, there are still several fundamental aspects of LRRK2 biology and function that remain unresolved at this time. This review will focus on the key questions of normal function of LRRK2 and how this might be related to the pathophysiology of PD.
KeywordsAutophagy Genetics Kinase activity Mutations
This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. For reasons of space, I unfortunately was not able to quote all of the primary literature and apologize to those colleagues whose work is mentioned in other reviews and not included directly here.
Compliance with Ethics Guidelines
Conflict of Interest
Mark R. Cookson declares that he has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 24.Henderson JL, Kormos BL, Hayward MM, et al. Discovery and preclinical profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. J Med Chem. 2014. doi: 10.1021/jm5014055.PubMedGoogle Scholar
- 68.•Tong Y, Giaime E, Yamaguchi H, et al. Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol Neurodegener. 2012;7:2. doi: 10.1186/1750-1326-7-2. This paper shows how phenotypes in LRRK2 knockout mice are affected by age. The exact interpretation of this data is not yet clear, but likely indicate that phenotypes are a mix of direct effect of loss of LRRK2 and compensatory changes in the same pathway.
- 69.Tong Y, Yamaguchi H, Giaime E, et al. Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice. Proc Natl Acad Sci U S A. 2010;107:9879–84. doi: 10.1073/pnas.1004676107.CrossRefPubMedCentralPubMedGoogle Scholar
- 72.••Manzoni C, Mamais A, Dihanich S, et al. Pathogenic Parkinson’s disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation. Biochem Biophys Res Commun. 2013;441:862–6. doi: 10.1016/j.bbrc.2013.10.159. Along with companion paper 71, the study by Manzoni et al is one of the first to show consistent biochemical effects of LRRK2 mutations in an autophagy related pathway. Of interest, the direction of effect of mutations is opposite that of kinase inhibitors, supporting the idea that mutations have a gain of normal function.
- 81.•Beilina A, Rudenko IN, Kaganovich A, et al. Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc Natl Acad Sci U S A. 2014. doi: 10.1073/pnas.1318306111. This paper, which is from my laboratory in collaboration with several other groups, indicates a potential relationship between LRRK2 and two proteins in GWAS-nominated regions for sporadic PD risk. Reference 90 also shows an interaction between LRRK2 and Rab7L1.
- 90.•Macleod DA, Rhinn H, Kuwahara T, et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron. 2013;77:425–39. doi: 10.1016/j.neuron.2012.11.033. This paper, along with reference 81, showed that LRRK2 interacts with the GWAS candidate gene Rab7L1. In this paper, the authors also indicate an effect on VPS35, part of the retromer complex and a gene for inherited PD (see references 92 and 93).
- 94.••Nalls MA, Pankratz N, Lill CM, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet. 2014;46:989–93. doi: 10.1038/ng.3043. This is the latest iteration of GWAS in PD, using data combined from many groups around the world and indicating that sporadic PD risk is influenced by more than twenty independent genetic factors.CrossRefPubMedCentralPubMedGoogle Scholar