scholarly journals Membrane targeting activates Leucine-rich repeat kinase 2 with differential effects on downstream Rab activation

2020 ◽  
Author(s):  
Jillian H. Kluss ◽  
Alexandra Beilina ◽  
Patrick A. Lewis ◽  
Mark R. Cookson ◽  
Luis Bonet-Ponce
Keyword(s):  
Parkinson’S Disease ◽  
Genetic Variation ◽  
Membrane Targeting ◽  
Potential Mechanism ◽  
Leucine Rich Repeat ◽  
Differential Effects ◽  
Lysosomal Membranes ◽  
Golgi Membranes ◽  
Sporadic Parkinson’S Disease ◽  
Perinuclear Area

ABSTRACTGenetic variation at the Leucine-rich repeat kinase 2 (LRRK2) locus contributes to risk of familial and sporadic Parkinson’s disease. Recent data have shown a robust association between localization to various membranes of the endolysosomal system and LRRK2 activation. However, the mechanism(s) underlying LRRK2 activation at endolysosomal membranes are still poorly understood. Here we artificially direct LRRK2 to six different membranes within the endolysosomal system. We demonstrate that LRRK2 is activated and able to phosphorylate three of its Rab substrates (Rab10, Rab12 and Rab29) at each compartment. However, we report differing localization of pRab10 and pRab12 at the lysosomal and Golgi membranes. Specifically, we found that pRab10 colocalizes with a sub-population of perinuclear LRRK2-positive Golgi/lysosomal compartments whereas pRab12 localized to all LRRK2-positive Golgi/lysosomal membranes across the cell. When organelle positioning is manipulated by sequestering lysosomes to the perinuclear area, pRab10 colocalization with LRRK2 significantly increases. We also show recruitment of JIP4, a pRab10 effector that we have recently linked to LYTL, after trapping LRRK2 at various membranes. Taken together, we demonstrate that the association of LRRK2 to membranous compartments is sufficient for its activation and Rab phosphorylation independent of membrane identity. Our system also identifies a potential mechanism underlying the distinct relationships between LRRK2 and its substrates Rab10 and Rab12.

scholarly journals LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis

2018 ◽  
Vol 115 (39) ◽  
pp. E9115-E9124 ◽  
Author(s):  
Tomoya Eguchi ◽  
Tomoki Kuwahara ◽  
Maria Sakurai ◽  
Tadayuki Komori ◽  
Tetta Fujimoto ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Crohn’S Disease ◽  
Human Diseases ◽  
Renal Tubules ◽  
Rab Gtpases ◽  
Leucine Rich Repeat ◽  
Lysosomal Membranes ◽  
Downstream Effectors ◽  
Lysosomal Targeting

Leucine-rich repeat kinase 2 (LRRK2) has been associated with a variety of human diseases, including Parkinson’s disease and Crohn’s disease, whereas LRRK2 deficiency leads to accumulation of abnormal lysosomes in aged animals. However, the cellular roles and mechanisms of LRRK2-mediated lysosomal regulation have remained elusive. Here, we reveal a mechanism of stress-induced lysosomal response by LRRK2 and its target Rab GTPases. Lysosomal overload stress induced the recruitment of endogenous LRRK2 onto lysosomal membranes and activated LRRK2. An upstream adaptor Rab7L1 (Rab29) promoted the lysosomal recruitment of LRRK2. Subsequent family-wide screening of Rab GTPases that may act downstream of LRRK2 translocation revealed that Rab8a and Rab10 were specifically accumulated on overloaded lysosomes dependent on their phosphorylation by LRRK2. Rab7L1-mediated lysosomal targeting of LRRK2 attenuated the stress-induced lysosomal enlargement and promoted lysosomal secretion, whereas Rab8 stabilized by LRRK2 on stressed lysosomes suppressed lysosomal enlargement and Rab10 promoted lysosomal secretion, respectively. These effects were mediated by the recruitment of Rab8/10 effectors EHBP1 and EHBP1L1. LRRK2 deficiency augmented the chloroquine-induced lysosomal vacuolation of renal tubules in vivo. These results implicate the stress-responsive machinery composed of Rab7L1, LRRK2, phosphorylated Rab8/10, and their downstream effectors in the maintenance of lysosomal homeostasis.

A common leucine-rich repeat kinase 2 gene mutation in familial and sporadic Parkinson's disease in Russia

2007 ◽  
Vol 14 (4) ◽  
pp. 413-417 ◽  
Author(s):  
S. N. Illarioshkin ◽  
M. I. Shadrina ◽  
P. A. Slominsky ◽  
E. V. Bespalova ◽  
T. B. Zagorovskaya ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gene Mutation ◽  
Leucine Rich Repeat ◽  
Sporadic Parkinson’S Disease

scholarly journals Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease

2010 ◽  
Vol 42 (9) ◽  
pp. 781-785 ◽  
Author(s):  
Taye H Hamza ◽  
Cyrus P Zabetian ◽  
Albert Tenesa ◽  
Alain Laederach ◽  
Jennifer Montimurro ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variation ◽  
Late Onset ◽  
Common Genetic Variation ◽  
Sporadic Parkinson’S Disease

NR4A2 genetic variation in sporadic Parkinson's disease: A genewide approach

2006 ◽  
Vol 21 (11) ◽  
pp. 1960-1963 ◽  
Author(s):  
Daniel G. Healy ◽  
Patrick M. Abou-Sleiman ◽  
Kourosh R. Ahmadi ◽  
Sonia Gandhi ◽  
Miratul M. Muqit ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variation ◽  
Sporadic Parkinson’S Disease

scholarly journals The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 598
Author(s):  
Jeswinder Sian-Hulsmann ◽  
Peter Riederer
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Viral Infections ◽  
Genetic Defect ◽  
Lewy Bodies ◽  
Common Denominator ◽  
Metabolic Disturbances ◽  
Trigger Factors ◽  
Protein Clearance ◽  
Sporadic Parkinson’S Disease

The risk of Parkinson’s disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson’s disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.

scholarly journals Lack of Association Between PLA2G6 Genetic Variation and Parkinson’s Disease: A Systematic Review

2020 ◽  
Vol Volume 16 ◽  
pp. 1755-1763
Author(s):  
Hongmei Liu ◽  
Yamin Yao ◽  
Hongbo Liu ◽  
Yanmin Peng ◽  
Juanjuan Ren ◽  
...  
Keyword(s):  
Systematic Review ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variation

scholarly journals Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson’s disease

Brain ◽  
2019 ◽  
Vol 142 (8) ◽  
pp. 2380-2401 ◽  
Author(s):  
Saurav Brahmachari ◽  
Saebom Lee ◽  
Sangjune Kim ◽  
Changqing Yuan ◽  
Senthilkumar S Karuppagounder ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Critical Role ◽  
Trna Synthetase ◽  
Loss Of Function ◽  
Substrate Protein ◽  
Finger Protein ◽  
Sporadic Parkinson’S Disease

Abstract α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson’s disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson’s disease, there is evidence that parkin is inactivated in sporadic Parkinson’s disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson’s disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson’s disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson’s disease and related α-synucleinopathies.

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