Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S
            <i>LRRK2</i>
            carriers

Fraser, Kyle; Moehle, Mark S.; Alcalay, Roy N.; West, Andrew B.

doi:10.1212/wnl.0000000000002436

Cited by 123 publications

(139 citation statements)

References 17 publications

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“…The G2019S mutation in the activation loop of the kinase domain produces a ~3–5 fold effect in some models and clinical samples(Fraser et al, 2016a), and the mutation is well-known to be incompletely penetrant in the Ashkenazi Jewish population (e.g., ~20–30% lifetime risk for PD)(Marder et al, 2015). The Y1699C variant and other ROC variants are nearly fully penetrant(Trinh et al, 2014), with only a few known examples of individuals greater than 65 years of age that do not have PD.…”

Section: Genetic and Biochemical Support Of A Gain-of-function Incmentioning

confidence: 99%

“…It is important to note that while the pSer935 site may reflect LRRK2 kinase inhibition, it is an indirect measure of LRRK2 kinase activity and expected phosphorylation of substrates. So far in model systems, pSer935 has mirrored the dephosphorylation of the LRRK2 substrate pSer1292 and pRab (Fraser et al, 2016a; Henry et al, 2015; Steger et al, 2016). …”

Section: Biomarkers For Lrrk2 Inhibition and Therapeutic Windows Fmentioning

confidence: 99%

“…Evaluation of LRRK2 expression via the Illumina mRNA human body map (Figure 3) demonstrates that the bulk of LRRK2 is probably in circulating cells. However, LRRK2 is also expressed in the brain and kidney, and LRRK2 can be measured in cerebral spinal fluid (CSF) in the brain as well as in urine(Fraser et al, 2016a; Fraser et al, 2013; Fraser et al, 2016b). While blood and urine can be procured relatively non-invasively in clinical populations, CSF at face-value may be ideal for measuring LRRK2 inhibition in the brain.…”

Section: Biomarkers For Lrrk2 Inhibition and Therapeutic Windows Fmentioning

confidence: 99%

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Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease

West

2017

Experimental Neurology

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In the translation of discoveries from the laboratory to the clinic, the track record in developing disease-modifying therapies in neurodegenerative disease is poor. A carefully designed development pipeline built from discoveries in both pre-clinical models and patient populations is necessary to optimize the chances for success. Genetic variation in the leucine-rich repeat kinase two gene (LRRK2) is linked to Parkinson disease (PD) susceptibility. Pathogenic mutations, particularly those in the LRRK2 GTPase (Roc) and COR domains, increase LRRK2 kinase activities in cells and tissues. In some PD models, small molecule LRRK2 kinase inhibitors that block these activities also provide neuroprotection. Herein, the genetic and biochemical evidence that supports the involvement of LRRK2 kinase activity in PD susceptibility is reviewed. Issues related to the definition of a therapeutic window for LRRK2 inhibition and the safety of chronic dosing are discussed. Finally, recommendations are given for a biomarker-guided initial entry of LRRK2 kinase inhibitors in PD patients. Four key areas must be considered for achieving neuroprotection with LRRK2 kinase inhibitors in PD: 1) identification of patient populations most likely to benefit from LRRK2 kinase inhibitors , 2) prioritization of superior LRRK2 small molecule inhibitors based on open disclosures of drug performance, 3) incorporation of biomarkers and empirical measures of LRRK2 kinase inhibition in clinical trials, and 4) utilization of appropriate efficacy measures guided in part by rigorous pre-clinical modeling. Meticulous and rational development decisions can potentially prevent incredibly costly errors and provide the best chances for LRRK2 inhibitors to slow the progression of PD.

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Section: Genetic and Biochemical Support Of A Gain-of-function Incmentioning

confidence: 99%

Section: Biomarkers For Lrrk2 Inhibition and Therapeutic Windows Fmentioning

confidence: 99%

Section: Biomarkers For Lrrk2 Inhibition and Therapeutic Windows Fmentioning

confidence: 99%

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Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease

West

2017

Experimental Neurology

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“…The kinase domain that harbors the most common LRRK2 mutation, G2019S, can direct intrinsic phosphorylation (ie, autophosphorylation) in and nearby the GTPase domain . Pathogenic LRRK2 mutations including the R1441C, Y1699C, and G2019S mutations increase autophosphorylated LRRK2 protein levels in model systems . One of the most abundant sites of autophosphorylation is the Ser‐1292 residue near the GTPase domain .…”

mentioning

confidence: 99%

“…Our previous work demonstrated that the LRRK2 protein can be purified from urinary exosomes in biobanked samples . Recently, we discovered that medicated PD patients with the G2019S‐ LRRK2 mutation show a ∼5‐fold elevation of autophosphorylated Ser(P)‐1292 LRRK2 protein in urinary exosomes when compared with noncarrier controls and medicated PD patients without the G0219S‐ LRRK2 mutation . LRRK2 autophosphorylation has not been previously evaluated in a larger series of idiopathic PD cases.…”

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confidence: 99%

Ser(P)‐1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson's disease

et al. 2016

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Background Mutations in Leucine-rich repeat kinase 2 (LRRK2) enhance levels of autophosphorylated LRRK2 protein and are the most common known cause of inherited Parkinson disease (PD). LRRK2 has been further implicated in susceptibility to idiopathic PD in genetic association studies. Objective To compare autophosphorylated Ser(P)-1292 LRRK2 levels from biobanked urine samples with clinical data in PD and controls. Methods Ser(P)-1292 LRRK2 levels were measured from urine exosome fractions from 79 PD and 79 neurologically healthy controls enrolled into the Parkinson Disease Biomarker Program at the University of Alabama at Birmingham. Results Ser(P)-1292 LRRK2 levels were higher in males than females (p<0.0001) and elevated in PD compared to controls (p=0.0014). Ser(P)-1292 LRRK2 levels were higher in PD cases with worse cognition and correlated with poor performance in MoCA (r=−0.2679 [−0.4628, −0.0482]), MDS-UPDRS subscales 1 and 2 (r=0.2239 [0.0014, 0,4252], 0.3404 [0.1276, 0.5233] respectively), Epworth Sleepiness Scale (r=0.3215 [0.1066, 0.5077]), and Modified Schwab and England Activities of Daily Living Scales (r=−0.4455 [−0.6078, −0.2475]). Ser(P)-1292 LRRK2 levels predicted those with worse cognitive impairment in PD patients with some success (c=0.73). Conclusions Urinary exosome Ser(P)-1292 LRRK2 levels are elevated in idiopathic PD and correlated with the severity of cognitive impairment and difficultly in accomplishing activities of daily living. These results implicate biochemical changes in LRRK2 in idiopathic PD.

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