Mutant LRRK2 Elicits Calcium Imbalance and Depletion of Dendritic Mitochondria in Neurons

Cherra, Salvatore J.; Steer, Erin; Gusdon, Aaron M.; Kiselyov, Kirill; Chu, Charleen T.

doi:10.1016/j.ajpath.2012.10.027

Cited by 174 publications

(181 citation statements)

References 74 publications

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“…These proteins are associated with a diversity of cellular processes, including protein chaperone activity, mitochondrial maintenance, and synaptic function. LRRK2 may impair degradation of ␣-synuclein (39) or synergistically impair mitochondrial function together with ␣-synuclein (40). Because the species of ␣-synuclein that underlies dopaminergic neurodegeneration is not clear, it was not possible for us to definitively assess a direct effect of G2019S-LRRK2 expression on toxic ␣-synuclein isoforms.…”

Section: Discussionmentioning

confidence: 99%

Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration

Daher

Abdelmotilib

et al. 2015

Journal of Biological Chemistry

187

196

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Background: LRRK2 kinase activity has been implicated in Parkinson disease (PD). Results: LRRK2 kinase inhibition attenuated neurodegeneration in LRRK2 transgenic and wild-type rats. Conclusion: Chronic inhibition of LRRK2 kinase activity is well tolerated in rats and provides neuroprotection from ␣-synuclein overexpression. Significance: These results warrant further studies that test the therapeutic potential of LRRK2 kinase inhibitors in additional PD models.

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Section: Discussionmentioning

confidence: 99%

Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration

Daher

Abdelmotilib

et al. 2015

Journal of Biological Chemistry

187

196

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“…56,57 Similarly, overexpression of mutant SNCA increases cellular autophagosomes, 58 which actively influences and impacts synaptic functions. Previous studies also demonstrate that both autophagy inducers and inhibitors serve as neuroprotectors against PD.…”

Section: Discussionmentioning

confidence: 99%

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

et al. 2015

Autophagy

110

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Keywords: autophagy, CDK5, melatonin, MPTP, SNCA, TH Abbreviations: ATG7, autophagy-related 7; BAFA1, bafilomycin A 1 ; CDK5, cyclin-dependent kinase 5; CDK5R1/p35/p25, cyclindependent kinase 5, regulatory subunit 1 (p35); DA, dopamine; DAPI, 4 0 ,6-diamidino-2-phenylindole; i.p, intraperitoneally; s.c, subcutaneously; ICV, intracerebroventricular; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; MAP2, microtube-associated protein 2; MPTP, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine; PD, Parkinson disease; PEBP1, phosphatidylethanolamine binding protein 1; PI, propidium iodide; SNc, substantia nigra pars compacta; SNCA/a-synuclein, synuclein, a (non A4 component of amyloid precursor); TH, tyrosine hydroxylase.Autophagy is involved in the pathogenesis of neurodegenerative diseases including Parkinson disease (PD). However, little is known about the regulation of autophagy in neurodegenerative process. In this study, we characterized aberrant activation of autophagy induced by neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and demonstrated that melatonin has a protective effect on neurotoxicity. We found an excessive activation of autophagy in monkey brain tissues and C6 cells, induced by MPTP, which is mediated by CDK5 (cyclin-dependent kinase 5). MPTP treatment significantly reduced total dendritic length and dendritic complexity of cultured primary cortical neurons and melatonin could reverse this effect. Decreased TH (tyrosine hydroxylase)-positive cells and dendrites of dopaminergic neurons in the substantia nigra pars compacta (SNc) were observed in MPTP-treated monkeys and mice. Along with decreased TH protein level, we observed an upregulation of CDK5 and enhanced autophagic activity in the striatum of mice with MPTP injection. These changes could be salvaged by melatonin treatment or knockdown of CDK5. Importantly, melatonin or knockdown of CDK5 reduced MPTP-induced SNCA/ a-synuclein aggregation in mice, which is widely thought to trigger the pathogenesis of PD. Finally, melatonin or knockdown of CDK5 counteracted the PD phenotype in mice induced by MPTP. Our findings uncover a potent role of CDK5-mediated autophagy in the pathogenesis of PD, and suggest that control of autophagic pathways may provide an important clue for exploring potential target for novel therapeutics of PD.

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“…Overexpression of G2019S ‐LRRK2 in SH‐SY5Y cells caused mitochondrial uncoupling, leading to reduced membrane potential and increased oxygen consumption 144. Primary mouse cortical neurons expressing either G2019S or R1441C‐ LRRK2 demonstrated increased mitophagy associated with altered calcium levels 145. Although human iPSC‐derived neurons carrying G2019S or R1441C ‐LRRK2 showed normal mitochondrial electron transport chain, they showed increased vulnerability to chemical stressors and disrupted mitochondrial movement 146.…”

Section: Lrrk2 Reactive Oxygen Species and Mitochondriamentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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Mutant LRRK2 Elicits Calcium Imbalance and Depletion of Dendritic Mitochondria in Neurons

Cited by 174 publications

References 74 publications

Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration

Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

Cellular processes associated with LRRK2 function and dysfunction

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