Cellular functions of LRRK2 implicate vesicular trafficking pathways in Parkinson's disease

2016 ◽  
Vol 44 (6) ◽  
pp. 1603-1610 ◽  
Author(s):  
Mark R. Cookson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Intracellular Trafficking ◽  
Small Gtpases ◽  
Vesicular Trafficking ◽  
Leucine Rich Repeat ◽  
Cellular Functions ◽  
Lrrk2 Gene ◽  
Rab Family ◽  
Cellular Compartments

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, associated with Parkinson's disease, have been shown to affect intracellular trafficking pathways in a variety of cells and organisms. An emerging theme is that LRRK2 can bind to multiple membranous structures in cells, and several recent studies have suggested that the Rab family of small GTPases might be important in controlling the recruitment of LRRK2 to specific cellular compartments. Once localized to membranes, LRRK2 then influences downstream events, evidenced by changes in the autophagy–lysosome pathway. Here, I will discuss available evidence that supports or challenges this outline, with a specific emphasis on those aspects of LRRK2 function that have been controversial or remain to be fully clarified.

Neuronal microtubules and proteins linked to Parkinson’s disease: a relevant interaction?

2019 ◽  
Vol 400 (9) ◽  
pp. 1099-1112 ◽  
Author(s):  
Alessandra M. Calogero ◽  
Samanta Mazzetti ◽  
Gianni Pezzoli ◽  
Graziella Cappelletti
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Intracellular Trafficking ◽  
Gene Mutations ◽  
Neuronal Loss ◽  
Leucine Rich Repeat ◽  
Microtubule Cytoskeleton ◽  
Pathological Conditions ◽  
Toxin Exposure ◽  
Relevant Interaction

AbstractNeuronal microtubules are key determinants of cell morphology, differentiation, migration and polarity, and contribute to intracellular trafficking along axons and dendrites. Microtubules are strictly regulated and alterations in their dynamics can lead to catastrophic effects in the neuron. Indeed, the importance of the microtubule cytoskeleton in many human diseases is emerging. Remarkably, a growing body of evidence indicates that microtubule defects could be linked to Parkinson’s disease pathogenesis. Only a few of the causes of the progressive neuronal loss underlying this disorder have been identified. They include gene mutations and toxin exposure, but the trigger leading to neurodegeneration is still unknown. In this scenario, the evidence showing that mutated proteins in Parkinson’s disease are involved in the regulation of the microtubule cytoskeleton is intriguing. Here, we focus on α-Synuclein, Parkin and Leucine-rich repeat kinase 2 (LRRK2), the three main proteins linked to the familial forms of the disease. The aim is to dissect their interaction with tubulin and microtubules in both physiological and pathological conditions, in which these proteins are overexpressed, mutated or absent. We highlight the relevance of such an interaction and suggest that these proteins could trigger neurodegeneration via defective regulation of the microtubule cytoskeleton.

scholarly journals Activation Mechanism of LRRK2 and Its Cellular Functions in Parkinson’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Katharina E. Rosenbusch ◽  
Arjan Kortholt
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Activation Mechanism ◽  
Leucine Rich Repeat ◽  
Cellular Functions ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
Interaction Domains ◽  
Effector Binding

Human LRRK2 (Leucine-Rich Repeat Kinase 2) has been associated with both familial and idiopathic Parkinson’s disease (PD). Although several LRRK2 mediated pathways and interaction partners have been identified, the cellular functions of LRRK2 and LRRK2 mediated progression of PD are still only partially understood. LRRK2 belongs to the group of Roco proteins which are characterized by the presence of a Ras-like G-domain (Roc), a C-terminal of Roc domain (COR), a kinase, and several protein-protein interaction domains. Roco proteins exhibit a complex activation mechanism involving intramolecular signaling, dimerization, and substrate/effector binding. Importantly, PD mutations in LRRK2 have been linked to a decreased GTPase and impaired kinase activity, thus providing putative therapeutic targets. To fully explore these potential targets it will be crucial to understand the function and identify the pathways responsible for LRRK2-linked PD. Here, we review the recent progress in elucidating the complex LRRK2 activation mechanism, describe the accumulating evidence that link LRRK2-mediated PD to mitochondrial dysfunction and aberrant autophagy, and discuss possible ways for therapeutically targeting LRRK2.

scholarly journals LRRK2 at the Crossroad of Aging and Parkinson’s Disease

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 505
Author(s):  
Eun-Mi Hur ◽  
Byoung Dae Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Late Onset ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Cellular Functions ◽  
Lewy Neurites ◽  
Clinical Presentations ◽  
Lrrk2 Gene ◽  
Cellular Dysfunction

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the widespread occurrence of proteinaceous inclusions known as Lewy bodies and Lewy neurites. The etiology of PD is still far from clear, but aging has been considered as the highest risk factor influencing the clinical presentations and the progression of PD. Accumulating evidence suggests that aging and PD induce common changes in multiple cellular functions, including redox imbalance, mitochondria dysfunction, and impaired proteostasis. Age-dependent deteriorations in cellular dysfunction may predispose individuals to PD, and cellular damages caused by genetic and/or environmental risk factors of PD may be exaggerated by aging. Mutations in the LRRK2 gene cause late-onset, autosomal dominant PD and comprise the most common genetic causes of both familial and sporadic PD. LRRK2-linked PD patients show clinical and pathological features indistinguishable from idiopathic PD patients. Here, we review cellular dysfunctions shared by aging and PD-associated LRRK2 mutations and discuss how the interplay between the two might play a role in PD pathologies.

scholarly journals LRRK2 in peripheral and central nervous system innate immunity: its link to Parkinson's disease

2017 ◽  
Vol 45 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Heyne Lee ◽  
William S. James ◽  
Sally A. Cowley
Keyword(s):  
Parkinson’S Disease ◽  
Central Nervous System ◽  
Parkinson's Disease ◽  
Innate Immunity ◽  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Cell Activation ◽  
Physiological Function ◽  
Leucine Rich Repeat ◽  
Lrrk2 Gene

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are found in familial and idiopathic cases of Parkinson's disease (PD), but are also associated with immune-related disorders, notably Crohn's disease and leprosy. Although the physiological function of LRRK2 protein remains largely elusive, increasing evidence suggests that it plays a role in innate immunity, a process that also has been implicated in neurodegenerative diseases, including PD. Innate immunity involves macrophages and microglia, in which endogenous LRRK2 expression is precisely regulated and expression is strongly up-regulated upon cell activation. This brief report discusses the current understanding of the involvement of LRRK2 in innate immunity particularly in relation to PD, critically examining its role in myeloid cells, particularly macrophages and microglia.

scholarly journals LRRK2 Screening in a Canadian Parkinson's Disease Cohort

2007 ◽  
Vol 34 (3) ◽  
pp. 336-338 ◽  
Author(s):  
D. A. Grimes ◽  
L. Racacho ◽  
F. Han ◽  
M. Panisset ◽  
D. E. Bulman
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Performance Liquid Chromatography ◽  
High Performance ◽  
Sequence Variants ◽  
Leucine Rich Repeat ◽  
Novel Mutations ◽  
Intronic Sequence ◽  
G2019s Mutation ◽  
Lrrk2 Gene

Background:Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have become the most common known cause for developing Parkinson's disease. The frequency of mutations described in the literature varies widely depending on the population studied with most reports focusing only on screening for the most common G2019S mutation in exon 41.Methods:In this study seven exons (19, 24, 25, 31, 35, 38, and 41) in LRRK2 where mutations have been reported were screened in 230 unselected Parkinson's disease patients using denaturing high-performance liquid chromatography.Results:The sequencing of samples with heteroduplex profiles revealed five novel and two known intronic sequence variants. In our cohort, we were unable to detect any of the known mutations in these exons or identify novel mutations within the LRRK2 gene.Conclusions:Therefore, despite the availability of diagnostic LRRK2 genetic testing it is unlikely to yield a positive result in this population.

scholarly journals Patient-control association study of the Leucine-Rich repeat kinase 2 (LRRK2) gene in South African Parkinson's disease patients

2013 ◽  
Vol 28 (14) ◽  
pp. 2039-2040 ◽  
Author(s):  
Soraya Bardien ◽  
Janine Blanckenberg ◽  
Lize van der Merwe ◽  
Matthew J. Farrer ◽  
Owen A. Ross
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Study ◽  
South African ◽  
Leucine Rich Repeat ◽  
Patient Control ◽  
Lrrk2 Gene ◽  
Control Association

scholarly journals Genetic Mutations and Mitochondrial Toxins Shed New Light on the Pathogenesis of Parkinson's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Shigeto Sato ◽  
Nobutaka Hattori
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Cultured Cells ◽  
Cellular Functions ◽  
Carbonyl Cyanide ◽  
Mitochondrial Toxins ◽  
Cellular Abnormalities ◽  
Mitochondrial Uncoupler

The cellular abnormalities in Parkinson's disease (PD) include mitochondrial dysfunction and oxidative damage, which are probably induced by both genetic predisposition and environmental factors. Mitochondrial dysfunction has long been implicated in the pathogenesis of PD. The recent discovery of genes associated with the etiology of familial PD has emphasized the role of mitochondrial dysfunction in PD. The discovery and increasing knowledge of the function of PINK1 and parkin, which are associated with the mitochondria, have also enhanced the understanding of cellular functions. The PINK1-parkin pathway is associated with quality control of the mitochondria, as determined in cultured cells treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which causes mitochondrial depolarization. To date, the use of mitochondrial toxins, for example, 1-methyl-4-phynyl-tetrahydropyridine (MPTP) and CCCP, has contributed to our understanding of PD. We review how these toxins and familial PD gene products are associated with and have enhanced our understanding of the role of mitochondrial dysfunction in PD.

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