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      Ser(P)-1292 LRRK2 in Urinary Exosomes is Elevated in Idiopathic Parkinson Disease

      research-article
      Author(s): , B.S. a , , B.S. a , , B.S. a , , M.D., MS b , , M.D., P.h.D a , , Ph.D. c , Parkinson’s Disease Biomarker Program Consortium, , Ph.D. a
      Publication date PMC-release:
      Journal: Movement disorders : official journal of the Movement Disorder Society
      Keywords: Biomarker, PARK8, Microvesicles, Cognitive decline

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          Abstract

          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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          Most cited references16

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          Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients.

          Doris Blum-Degena, Thomas Muller, Wilfried Kuhn … (1995)
          Interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), and interleukin-6 (IL-6) were measured in the cerebrospinal fluid (CSF) and plasma of 12 control subjects, 11 sporadic Alzheimer's disease (AD) and 22 de novo Parkinson's disease (PD) patients using high sensitivity enzyme-linked immunosorbent assays (ELISA). IL-1 beta and IL-6 contents were significantly elevated in the CSF of de novo PD and AD patients in comparison to the control group. In contrast, the plasma levels were not significantly affected. IL-2 contents in the CSF and plasma samples were unchanged in the three groups compared. Because the two cytokines IL-1 beta and IL-6 are known to play a key role in the interaction between the nervous and immune system, e.g. in the so-called acute phase response, our results support the involvement of immunological events in the complex process of neurodegeneration in AD and PD.
          Article 0 comments Cited 227 times – based on 0 reviews     Review now
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            Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations.

            Xingrong Liu, Kimberly Scearce-Levie, Z. M. Sheng … (2012)
            Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson's disease (PD). Although biochemical studies have shown that certain PD mutations confer elevated kinase activity in vitro on LRRK2, there are no methods available to directly monitor LRRK2 kinase activity in vivo. We demonstrate that LRRK2 autophosphorylation on Ser(1292) occurs in vivo and is enhanced by several familial PD mutations including N1437H, R1441G/C, G2019S, and I2020T. Combining two PD mutations together further increases Ser(1292) autophosphorylation. Mutation of Ser(1292) to alanine (S1292A) ameliorates the effects of LRRK2 PD mutations on neurite outgrowth in cultured rat embryonic primary neurons. Using cell-based and pharmacodynamic assays with phosphorylated Ser(1292) as the readout, we developed a brain-penetrating LRRK2 kinase inhibitor that blocks Ser(1292) autophosphorylation in vivo and attenuates the cellular consequences of LRRK2 PD mutations in vitro. These data suggest that Ser(1292) autophosphorylation may be a useful indicator of LRRK2 kinase activity in vivo and may contribute to the cellular effects of certain PD mutations.
            Article 0 comments Cited 165 times – based on 0 reviews     Review now
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              Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.

              Xiaojie Li, Robert Moore, Shaida A. Andrabi … (2007)
              Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease indistinguishable from idiopathic disease. The mechanisms whereby missense alterations in the LRRK2 gene initiate neurodegeneration remain unknown. Here, we demonstrate that seven of 10 suspected familial-linked mutations result in increased kinase activity. Functional and disease-associated mutations in conserved residues reveal the critical link between intrinsic guanosine triphosphatase (GTPase) activity and downstream kinase activity. LRRK2 kinase activity requires GTPase activity, whereas GTPase activity functions independently of kinase activity. Both LRRK2 kinase and GTPase activity are required for neurotoxicity and potentiate peroxide-induced cell death, although LRRK2 does not function as a canonical MAP-kinase-kinase-kinase. These results suggest a link between LRRK2 kinase activity and pathogenic mechanisms relating to neurodegeneration, further supporting a gain-of-function role for LRRK2 mutations.
              Article 0 comments Cited 164 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 8610688
                Journal ID (pubmed-jr-id): 5937
                Journal ID (nlm-ta): Mov Disord
                Journal ID (iso-abbrev): Mov. Disord.
                Title: Movement disorders : official journal of the Movement Disorder Society
                ISSN (Print): 0885-3185
                ISSN (Electronic): 1531-8257
                Publication date Nihms-submitted: 10 May 2016
                Publication date (Print): October 2016
                Publication date PMC-release: 01 October 2017
                Volume: 31
                Issue: 10
                Pages: 1543-1550
                Affiliations
                [a ]Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Alabama
                [b ]Department of Neurology, Columbia University, New York
                [c ]Department of Biostatistics, University of Alabama at Birmingham, Alabama
                Author notes
                [1 ]Corresponding author information: Andrew West, 1719 6 th Ave S., Birmingham, AL 35294, Phone (205 996-7697), Fax (205 996-6580), abwest@ 123456uab.edu
                [*]

                PDBP consortium consists of multiple scientists that contributed to study design and are listed at http://pdbp.ninds.nih.gov/projects-we-support

                Article
                Accession ID: PMC5053851 Pmcid ID: PMC5053851 Pmc-uid ID: 5053851 Manuscript ID: nihpa785284
                DOI: 10.1002/mds.26686
                PMC ID: 5053851
                PubMed ID: 27297049
                SO-VID: 5fefd5b3-d00d-4a45-9df0-fdc64fdbe0a1
                History
                Categories
                Subject: Article

                Keywords: Cognitive decline,Biomarker,PARK8,Microvesicles
                Data availability:
                Keywords: Cognitive decline, Biomarker, PARK8, Microvesicles

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