The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway

Pedro, José Manuel Bravo-San; Niso-Santano, Mireia; Gómez-Sánchez, Rubén; Pizarro-Estrella, Elisa; Aiastui, Ana; Gorostidi, Ana; Climent, Vicente; Maturana, Rakel López de; Sánchez‐Pernaute, Rosario; Munáin, Adolfo López de; Fuentes, José; González‐Polo, Rosa A.

doi:10.1007/s00018-012-1061-y

Cited by 147 publications

(128 citation statements)

References 61 publications

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“…The MAPK/ERK pathway has been shown to inhibit autophagy in response to a number of signals (71,72). We observed activation of MAPK/ERK pathway (shown below) in response to recombinant MsmRv3242c infection in macrophages.…”

Section: The Increase In Intracellular Survival By Rv3242c and Mimg Imentioning

confidence: 55%

A Mycobacterial Phosphoribosyltransferase Promotes Bacillary Survival by Inhibiting Oxidative Stress and Autophagy Pathways in Macrophages and Zebrafish

Mohanty

Jagannathan

Ganguli

et al. 2015

Journal of Biological Chemistry

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Background: Several Mycobacterium tuberculosis glycoproteins are involved in tuberculosis pathogenesis. Results: Mycobacterium tuberculosis Rv3242c and Mycobacterium marinum mimG enhance bacillary survival by inhibiting oxidative stress and autophagy pathways in macrophages and zebrafish. Conclusion: Rv3242c and mimG aid intracellular bacterial persistence by modulating host immune responses. Significance: This study has identified a novel virulence factor, which can be considered as drug target for tuberculosis treatment.

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Section: The Increase In Intracellular Survival By Rv3242c and Mimg Imentioning

confidence: 55%

A Mycobacterial Phosphoribosyltransferase Promotes Bacillary Survival by Inhibiting Oxidative Stress and Autophagy Pathways in Macrophages and Zebrafish

Mohanty

Jagannathan

Ganguli

et al. 2015

Journal of Biological Chemistry

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“…Other studies have reported autophagy upregulation following overexpression of LRRK2 G2019S by an ERK1/2-mediated mechanism (37,38). Perhaps the most prominent link between autophagy and familial forms of PD comes from studies of the roles of PTENinduced putative kinase 1 (PINK1, also known as PARK6) and Parloss, and lysosome pathology (15).…”

Section: G2019smentioning

confidence: 99%

Autophagy and neurodegeneration

Frake¹,

Ricketts²,

Menzies³

et al. 2015

J. Clin. Invest.

300

251

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“…The alteration of this MAPK pathway was considered responsible for the G2019S ‐LRRK2 mediated increase in basal autophagy 74.…”

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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The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway

Cited by 147 publications

References 61 publications

A Mycobacterial Phosphoribosyltransferase Promotes Bacillary Survival by Inhibiting Oxidative Stress and Autophagy Pathways in Macrophages and Zebrafish

A Mycobacterial Phosphoribosyltransferase Promotes Bacillary Survival by Inhibiting Oxidative Stress and Autophagy Pathways in Macrophages and Zebrafish

Autophagy and neurodegeneration

Cellular processes associated with LRRK2 function and dysfunction

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