LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity

Parisiadou, Loukia; Yu, Jia; Sgobio, Carmelo; Xie, Chengsong; Liu, Guoxiang; Sun, Lixin; Gu, Xin-Xing; Lin, Xian; Crowley, Nicole A.; Lovinger, David M.; Cai, Huaibin

doi:10.1038/nn.3636

Cited by 170 publications

(230 citation statements)

References 60 publications

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“…However, the G2385R LRRK2 variant does not induce neurite shortening (at least in M17 neuroblastoma cells), and even alleviated the effect of G2019S mutant when present on the same construct [73]. Furthermore, the effects of mutant LRRK2 on neurite length have a limited developmental window [55]. It might be that altered development of neurons changes their later sensitivity to the PD process, but that hypothesis is difficult to assess without an in vivo model that shows both neurite length changes and neurodegeneration, both of which are lacking in current models.…”

Section: Effects Of Lrrk2 On Cellular Phenotypes and Physiologymentioning

confidence: 99%

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Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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Section: Effects Of Lrrk2 On Cellular Phenotypes and Physiologymentioning

confidence: 99%

“…The physiological function of LRRK2 is unknown, but LRRK2 is involved in autophagy [49,50], vesicle sorting and trafficking [51,52], dopamine homeostasis [53,54], dopamine receptor activation, synaptogenesis [55], and cytoskeleton dynamics (Fig. 2) [56,57].…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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“…Aberrant localization of protein kinase A in knockout mice increased cofilin and glutamate receptor 1 (GluR1) phosphorylation, thus interfering with synaptogenesis and dopamine signalling through the dopamine receptor Drd1 90.…”

Section: Signalling Pathways Through Lrrk2mentioning

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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“…1) [18].LRRK2 only through cofilin to control the development of dendritic spines. Suggesting that the researchers may be able to signal the LRRK2-PKA-Cofilin-Transduction pathway to find a therapeutic target for the treatment of PD [18]. [18].…”

Section: Function Of Adf/cofilin Family Proteins In Central Nervous Smentioning

confidence: 99%

“…Suggesting that the researchers may be able to signal the LRRK2-PKA-Cofilin-Transduction pathway to find a therapeutic target for the treatment of PD [18]. [18]. ADF / Cofilin Family of Proteins with Aging.…”

Section: Function Of Adf/cofilin Family Proteins In Central Nervous Smentioning

confidence: 99%

Advances in the Role of ADF / Cofilin in Central Nervous System

Li¹,

Wang²,

Li³

et al. 2017

Proceedings of the 2017 2nd International Symposium on Advances in Electrical, Electronics and Computer Engineering (ISAEECE 20

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Abstract. Extracellular signaling regulates cell motility, growth, differentiation, gene expression, polarization and death. Activation of Actin cytoskeleton is an important condition for the occurrence of these cellular responses and morphological changes.The ADF / Cofilin family of proteins is an important regulator of Actin cytoskeleton regulation, recent studies have shown that changes in the content and activity of these proteins are associated with a variety of neurological diseases such as Parkinson's disease, Alzheimer's disease etc. Exercise can change the activity of the family protein and help to delay or cure the disease. This article reviews the role of ADF / Cofilin family proteins in the nervous system in order to provide new ideas for future disease treatment.

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LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity

Cited by 170 publications

References 60 publications

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Cellular processes associated with LRRK2 function and dysfunction

Advances in the Role of ADF / Cofilin in Central Nervous System

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