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.

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 The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation

2012 ◽  
Vol 446 (1) ◽  
pp. 99-111 ◽  
Author(s):  
Iakov N. Rudenko ◽  
Alice Kaganovich ◽  
David N. Hauser ◽  
Aleksandra Beylina ◽  
Ruth Chia ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Missense Mutations ◽  
Leucine Rich Repeat ◽  
Loss Of Function ◽  
Partial Loss ◽  
G2019s Mutation ◽  
Enzymatic Function ◽  
C Terminus

Autosomal-dominant missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a common genetic cause of PD (Parkinson's disease). LRRK2 is a multidomain protein with kinase and GTPase activities. Dominant mutations are found in the domains that have these two enzyme activities, including the common G2019S mutation that increases kinase activity 2–3-fold. However, there is also a genetic variant in some populations, G2385R, that lies in a C-terminal WD40 domain of LRRK2 and acts as a risk factor for PD. In the present study we show that the G2385R mutation causes a partial loss of the kinase function of LRRK2 and deletion of the C-terminus completely abolishes kinase activity. This effect is strong enough to overcome the kinase-activating effects of the G2019S mutation in the kinase domain. Hsp90 (heat-shock protein of 90 kDa) has an increased affinity for the G2385R variant compared with WT (wild-type) LRRK2, and inhibition of the chaperone binding combined with proteasome inhibition leads to association of mutant LRRK2 with high molecular mass native fractions that probably represent proteasome degradation pathways. The loss-of-function of G2385R correlates with several cellular phenotypes that have been proposed to be kinase-dependent. These results suggest that the C-terminus of LRRK2 plays an important role in maintaining enzymatic function of the protein and that G2385R may be associated with PD in a way that is different from kinase-activating mutations. These results may be important in understanding the differing mechanism(s) by which mutations in LRRK2 act and may also have implications for therapeutic strategies for PD.

Targeting leucine-rich repeat kinase 2 (LRRK2) for the treatment of Parkinson's disease

2019 ◽  
Vol 11 (15) ◽  
pp. 1953-1977 ◽  
Author(s):  
Sofia Domingos ◽  
Teresa Duarte ◽  
Lucília Saraiva ◽  
Rita C Guedes ◽  
Rui Moreira
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Leucine Rich Repeat ◽  
Serine Threonine Kinase ◽  
Drug Candidates ◽  
Cellular Processes ◽  
Pathogenic Variants ◽  
Lrrk2 Kinase ◽  
Relationship Of

Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine kinase involved in multiple cellular processes and signaling pathways. LRRK2 mutations are associated with autosomal-inherited Parkinson's disease (PD), and evidence suggests that LRRK2 pathogenic variants generally increase kinase activity. Therefore, inhibition of LRRK2 kinase function is a promising therapeutic strategy for PD treatment. The search for drug-like molecules capable of reducing LRRK2 kinase activity in PD led to the design of selective LRRK2 inhibitors predicted to be within the CNS drug-like space. This review highlights the journey that translates chemical tools for interrogating the role of LRRK2 in PD into promising drug candidates, addressing the challenges in discovering selective and brain-penetrant LRRK2 modulators and exploring the structure–activity relationship of distinct LRRK2 inhibitors.

scholarly journals Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

Cell Research ◽  
2019 ◽  
Vol 29 (4) ◽  
pp. 313-329 ◽  
Author(s):  
Adam Schaffner ◽  
Xianting Li ◽  
Yacob Gomez-Llorente ◽  
Emmanouela Leandrou ◽  
Anna Memou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Vitamin B12 ◽  
Kinase Activity ◽  
Allosteric Regulation ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase 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 The activities of LRRK2 and GCase are positively correlated in clinical biospecimens and experimental models of Parkinson’s disease

2021 ◽  
Author(s):  
Maria Kedariti ◽  
Emanuele Frattini ◽  
Pascale Baden ◽  
Susanna Cogo ◽  
Laura Civiero ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Experimental Models ◽  
Cellular Functions ◽  
Gene Encoding ◽  
Cellular Models ◽  
Lrrk2 Kinase ◽  
The Impact ◽  
Lrrk2 Kinase Activity

AbstractLRRK2 is a kinase involved in different cellular functions, including autophagy, endolysosomal pathways and vesicle trafficking. Mutations in LRRK2 cause autosomal dominant forms of Parkinson’s disease (PD). Heterozygous mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), are the most common genetic risk factors for PD. Moreover, GCase function is altered in idiopathic PD and in other genetic forms of the disease. Recent work suggests that LRRK2 kinase activity can regulate GCase function. However, both a positive and a negative correlation have been described. To gain insights into the impact of LRRK2 on GCase, we investigated GCase levels and activity in LRRK2 G2019S knockin mice, in clinical biospecimens from PD patients carrying this mutation and in patient-derived cellular models. In these models we found a positive correlation between the activities of LRRK2 and GCase, which was further confirmed in cell lines with genetic and pharmacological manipulation of LRRK2 kinase activity. Overall, our study indicates that LRRK2 kinase activity affects both the levels and the catalytic activity of GCase.

Role of LRRK2 kinase activity in the pathogenesis of Parkinson's disease

2012 ◽  
Vol 40 (5) ◽  
pp. 1058-1062 ◽  
Author(s):  
Elisa Greggio
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Complex Molecule ◽  
Disease Onset ◽  
Missense Mutations ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

Interest in studying the biology of LRRK2 (leucine-rich repeat kinase 2) started in 2004 when missense mutations in the LRRK2 gene were linked to an inherited form of Parkinson's disease with clinical and pathological presentation resembling the sporadic syndrome. LRRK2 is a complex molecule containing domains implicated in protein interactions, as well as kinase and GTPase activities. The observation that the common G2019S mutation increases kinase activity in vitro suggests that altered phosphorylation of LRRK2 targets may have pathological outcomes. Given that protein kinases are ideal targets for drug therapies, much effort has been directed at understanding the role of LRRK2 kinase activity on disease onset. However, no clear physiological substrates have been identified to date, indicating that much research is still needed to fully understand the signalling pathways orchestrated by LRRK2 and deregulated under pathological conditions.

scholarly journals 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization

2010 ◽  
Vol 430 (3) ◽  
pp. 393-404 ◽  
Author(s):  
R. Jeremy Nichols ◽  
Nicolas Dzamko ◽  
Nicholas A. Morrice ◽  
David G. Campbell ◽  
Maria Deak ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Kinase ◽  
Inclusion Bodies ◽  
Kinase Activity ◽  
Protein Isoforms ◽  
Protein Kinase Activity ◽  
Leucine Rich Repeat ◽  
Pathogenic Mutations ◽  
Mouse Tissues

LRRK2 (leucine-rich repeat protein kinase 2) is mutated in a significant number of Parkinson's disease patients, but still little is understood about how it is regulated or functions. In the present study we have demonstrated that 14-3-3 protein isoforms interact with LRRK2. Consistent with this, endogenous LRRK2 isolated from Swiss 3T3 cells or various mouse tissues is associated with endogenous 14-3-3 isoforms. We have established that 14-3-3 binding is mediated by phosphorylation of LRRK2 at two conserved residues (Ser910 and Ser935) located before the leucine-rich repeat domain. Our results suggests that mutation of Ser910 and/or Ser935 to disrupt 14-3-3 binding does not affect intrinsic protein kinase activity, but induces LRRK2 to accumulate within discrete cytoplasmic pools, perhaps resembling inclusion bodies. To investigate links between 14-3-3 binding and Parkinson's disease, we studied how 41 reported mutations of LRRK2 affected 14-3-3 binding and cellular localization. Strikingly, we found that five of the six most common pathogenic mutations (R1441C, R1441G, R1441H, Y1699C and I2020T) display markedly reduced phosphorylation of Ser910/Ser935 thereby disrupting interaction with 14-3-3. We have also demonstrated that Ser910/Ser935 phosphorylation and 14-3-3 binding to endogenous LRRK2 is significantly reduced in tissues of homozygous LRRK2(R1441C) knock-in mice. Consistent with 14-3-3 regulating localization, all of the common pathogenic mutations displaying reduced 14-3-3-binding accumulated within inclusion bodies. We also found that three of the 41 LRRK2 mutations analysed displayed elevated protein kinase activity (R1728H, ~2-fold; G2019S, ~3-fold; and T2031S, ~4-fold). These results provide the first evidence suggesting that 14-3-3 regulates LRRK2 and that disruption of the interaction of LRRK2 with 14-3-3 may be linked to Parkinson's disease.

scholarly journals Activation Mechanism of LRRK2 and Its Cellular Functions in Parkinson’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Katharina E. Rosenbusch ◽  
Arjan Kortholt
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Activation Mechanism ◽  
Leucine Rich Repeat ◽  
Cellular Functions ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
Interaction Domains ◽  
Effector Binding

Human LRRK2 (Leucine-Rich Repeat Kinase 2) has been associated with both familial and idiopathic Parkinson’s disease (PD). Although several LRRK2 mediated pathways and interaction partners have been identified, the cellular functions of LRRK2 and LRRK2 mediated progression of PD are still only partially understood. LRRK2 belongs to the group of Roco proteins which are characterized by the presence of a Ras-like G-domain (Roc), a C-terminal of Roc domain (COR), a kinase, and several protein-protein interaction domains. Roco proteins exhibit a complex activation mechanism involving intramolecular signaling, dimerization, and substrate/effector binding. Importantly, PD mutations in LRRK2 have been linked to a decreased GTPase and impaired kinase activity, thus providing putative therapeutic targets. To fully explore these potential targets it will be crucial to understand the function and identify the pathways responsible for LRRK2-linked PD. Here, we review the recent progress in elucidating the complex LRRK2 activation mechanism, describe the accumulating evidence that link LRRK2-mediated PD to mitochondrial dysfunction and aberrant autophagy, and discuss possible ways for therapeutically targeting LRRK2.

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