scholarly journals Identification of protein phosphatase 1 as a regulator of the LRRK2 phosphorylation cycle

2013 ◽  
Vol 456 (1) ◽  
pp. 119-128 ◽  
Author(s):  
Evy Lobbestael ◽  
Jing Zhao ◽  
Iakov N. Rudenko ◽  
Aleksandra Beylina ◽  
Fangye Gao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Leucine Rich Repeat ◽  
Kinase Inhibition ◽  
Disease Modifying Therapy ◽  
Mutant Lrrk2 ◽  
Lrrk2 Kinase ◽  
Disease Modifying ◽  
Insight Into

Protein phosphatase 1 is responsible for the dephosphorylation of Parkinson's disease-linked LRRK2 (leucine-rich repeat kinase 2) mutants and after pharmacological LRRK2 kinase inhibition. This provides insight into the mutant LRRK2 pathomechanisms and the cellular consequences of a potential disease-modifying therapy.

scholarly journals mTOR independent alteration in ULK1 Ser758 phosphorylation following chronic LRRK2 kinase inhibition

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Claudia Manzoni ◽  
Adamantios Mamais ◽  
Sybille Dihanich ◽  
Marc P.M. Soutar ◽  
Helene Plun-Favreau ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Protein Phosphorylation ◽  
Kinase Activity ◽  
Central Component ◽  
Leucine Rich Repeat ◽  
Kinase Inhibition ◽  
Enzymatic Function ◽  
Lrrk2 Kinase ◽  
Pathway Regulation ◽  
Mtor Complex 1

Unc-51 Like Kinase 1 (ULK1) is a critical regulator of the biogenesis of autophagosomes, the central component of the catabolic macroautophagy pathway. Regulation of ULK1 activity is dependent upon several phosphorylation events acting to repress or activate the enzymatic function of this protein. Phosphorylation of Ser758 ULK1 has been linked to repression of autophagosome biogenesis and was thought to be exclusively dependent upon mTOR complex 1 kinase activity. In the present study, a novel regulation of Ser758 ULK1 phosphorylation is reported following prolonged inhibition of the Parkinson’s disease linked protein leucine rich repeat kinase 2 (LRRK2). Here, modulation of Ser758 ULK1 phosphorylation following LRRK2 inhibition is decoupled from the repression of autophagosome biogenesis and independent of mTOR complex 1 activity.

Phosphorylation of LRRK2: from kinase to substrate

2012 ◽  
Vol 40 (5) ◽  
pp. 1102-1110 ◽  
Author(s):  
Evy Lobbestael ◽  
Veerle Baekelandt ◽  
Jean-Marc Taymans
Keyword(s):  
Kinase Activity ◽  
Pathological Process ◽  
Rapid Decrease ◽  
Leucine Rich Repeat ◽  
Phosphorylated Protein ◽  
Pathogenic Variants ◽  
Disease Protein ◽  
Lrrk2 Kinase ◽  
Disease Modifying ◽  
Lrrk2 Kinase Activity

The PD (Parkinson's disease) protein LRRK2 (leucine-rich repeat kinase 2) occurs in cells as a highly phosphorylated protein, with the majority of phosphosites clustering in the region between the ankyrin repeat and leucine-rich repeat domains. The observation that several pathogenic variants of LRRK2 display strongly reduced cellular phosphorylation suggests that phosphorylation of LRRK2 is involved in the PD pathological process. Furthermore, treatment of cells with inhibitors of LRRK2 kinase activity, which are currently considered as potential disease-modifying therapeutics for PD, leads to a rapid decrease in the phosphorylation levels of LRRK2. For these reasons, understanding the cellular role and regulation of LRRK2 as a kinase and as a substrate has become the focus of intense investigation. In the present review, we discuss what is currently known about the cellular phosphorylation of LRRK2 and how this relates to its function and dysfunction.

scholarly journals Fibroblast Biomarkers of Sporadic Parkinson’s Disease and LRRK2 Kinase Inhibition

2015 ◽  
Vol 53 (8) ◽  
pp. 5161-5177 ◽  
Author(s):  
G. A. Smith ◽  
J. Jansson ◽  
E. M. Rocha ◽  
T. Osborn ◽  
P. J. Hallett ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Inhibition ◽  
Sporadic Parkinson’S Disease ◽  
Lrrk2 Kinase
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