Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson's-Disease-Related Mutant α-synuclein

Lin, Xian; Parisiadou, Loukia; Gu, Xin-Xing; Wang, Lizhen; Shim, Hoon; Sun, Lixin; Xie, Chengsong; Long, Cai Xia; Yang, Wan Shan; Ding, Jinhui; Chen, Zsu-Zsu; Gallant, Paul E.; Tao-Cheng, Jung-Hwa; Troncoso, Juan C.; Liu, Zhihua; Li, Zheng; Cai, Huaibin

doi:10.1016/j.neuron.2009.11.006

Cited by 466 publications

(514 citation statements)

References 52 publications

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“…In G2019S transgenic mice, ultrastructure examination showed an accumulation of damaged mitochondria, consistent with altered mitophagy in aged mice 143. In a double‐transgenic mouse expressing G2019S ‐LRRK2 and A53T α‐synuclein, structural and functional abnormalities within the brain mitochondria suggested LRRK2 to induce a mitochondrial phenotype 121. Overexpression of G2019S ‐LRRK2 in SH‐SY5Y cells caused mitochondrial uncoupling, leading to reduced membrane potential and increased oxygen consumption 144.…”

Section: Lrrk2 Reactive Oxygen Species and Mitochondriamentioning

confidence: 88%

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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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Section: Lrrk2 Reactive Oxygen Species and Mitochondriamentioning

confidence: 88%

“…LRRK2 was found to be associated with membranous structures and vesicles in the mammalian brain 120 and enriched in the Golgi complex 42, 94 at the extent that mice with wild‐type and G2019S ‐LRRK2 overexpression presented fragmentation of the Golgi complex 121.…”

Section: Lrrk2 Function In Vesicle Dynamics and Retromer Functionmentioning

confidence: 98%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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“…Indeed protein inclusions have been suggested to be toxic, protective or simply correlate with the disease without influencing its pathogenesis. Despite this, many reports show that removal of protein aggregates has a protective role on neurons and can lead to symptom regression [39,[45][46][47]. Interestingly a common feature of accumulated proteins in proteinopathies is that they are ubiquitinated [48][49][50], raising the question of why they are then not eliminated through the proteasome.…”

Section: Discussionmentioning

confidence: 99%

Protein repertoire impact of Ubiquitin–Proteasome System impairment: Insight into the protective role of beta-estradiol

D'Alessandro¹,

D’Aguanno²,

Cencioni³

et al. 2012

Journal of Proteomics

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The Ubiquitin-Proteasome System (UPS) and the Autophagy-Lysosome Pathways (ALP) are key mechanisms for cellular homeostasis sustenance and protein clearance. A wide number of Neurodegenerative Diseases (NDs) are tied with UPS impairment and have been also described as proteinopathies caused by aggregate-prone proteins, not efficiently removed by proteasome.Despite the large knowledge on proteasome biological role, molecular mechanisms associated with its impairment are still blur. We have pursued a comprehensive proteomic investigation to evaluate the phenotypic rearrangements in protein repertoires associated with a UPS blockage. Unsupervised meta-analysis of the collected proteomic data revealed that all the identified proteins relate each other in a functional network centered on beta-estradiol. Moreover we showed that treatment of cells with beta-estradiol resulted in aggregate removal and increased cell survival due to activation of the autophagic pathway. Our data may provide the molecular basis for the use of beta-estradiol in neurodegenerative disorders by induction of protein aggregate removal.

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“…From inducible mouse models of neurodegeneration it is known that a continuous expression of the pathological protein is required to maintain inclusions and the neurodegenerative phenotype, raising the possibility that diseases caused by aggregating proteins (such as HD) may be reversible. [74][75][76][77][78][79][80][81][82] It seems like the role of ALFY in aggregate clearance can be extended to other disease-associated aggregate-prone proteins. ALFY depletion inhibited clearance of mutant a-synuclein A53T, linked to Parkinson's disease, and co-immunoprecipitation experiments revealed that a-synuclein is detected in the same complex as Atg5 and ALFY.…”

Section: Alfy and Neurodegenerationmentioning

confidence: 99%

The role of ALFY in selective autophagy

2012

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Autophagy, a highly conserved lysosomal degradation pathway, was initially characterized as a bulk degradation system induced in response to starvation. In recent years, autophagy has emerged also as a highly selective pathway, targeting various cargoes such as aggregated proteins and damaged organelles for degradation. The key factors involved in selective autophagy are autophagy receptors and adaptor proteins, which connect the cargo to the core autophagy machinery. In this review, we discuss the current knowledge about the only mammalian adaptor protein identified thus far, autophagy-linked FYVE protein (ALFY). ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. We also comment on the possible role of ALFY in the context of disease.

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Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson's-Disease-Related Mutant α-synuclein

Cited by 466 publications

References 52 publications

Cellular processes associated with LRRK2 function and dysfunction

Cellular processes associated with LRRK2 function and dysfunction

Protein repertoire impact of Ubiquitin–Proteasome System impairment: Insight into the protective role of beta-estradiol

The role of ALFY in selective autophagy

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