Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients

Fernández, Belén; Ordóñez, Antonio Jesús Lara; Fdez, Elena; Mutez, Eugénie; Comptdaer, Thomas; Leghay, Coline; Kreisler, Alexandre; Simonin, C.; Vandewynckel, Laurine; Defebvre, Luc; Destée, Alain; Bleuse, S.; Taymans, Jean-Marc; Chartier-Harlin, Marie-Christine; Hilfiker, Sabine

doi:10.1042/bcj20190315

Cited by 34 publications

(57 citation statements)

References 43 publications

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“…Therefore, we investigated whether pRab10 or pRab8 level was elevated with the LRRK2 G2019S mutation in patient-derived cells. Consistent with previous reports 18,33 , there was no significant difference in levels of pRab10 between PD LRRK2 G2019S patient-derived and healthy control cells (Supplemental Fig. S3).…”

Section: Rab8 and Rab10 Phosphorylation In Control And Lrrk2 G2019s Psupporting

confidence: 92%

“…While changes in mtDNA damage levels were robustly detected following LRRK2 kinase inhibition in LRRK2 G2019S patient-derived cells, this was not the case in healthy control LCLs. It is possible that wild-type LRRK2 kinase activity in control cells is either low to non-detectable, as has been reported by our group and others with measuring endogenous levels by either immunoblotting or proximity ligation assay via LRRK2 pSer1292 10,14,33,47 . Thus changes in mtDNA damage levels following LRRK2 kinase inhibition in control cells may be minimal.…”

Section: Discussionmentioning

confidence: 73%

“…To date, LRRK2 or Rab10 phosphorylation show no consistent differences between healthy controls and idiopathic PD, making these biomarkers unlikely candidates for patient stratification. Recently, centrosomal cohesion alterations could be detected in both LRRK2 G2019S LCLs and a subset of idiopathic PD patient samples 48 . These cohesion deficits in subjects with idiopathic PD were reverted with a LRRK2 kinase inhibitor, despite lack of increased LRRK2 pSer1292 using a proximity ligation-based assay 48 .…”

Section: Discussionmentioning

confidence: 99%

“…Rab10 phosphorylation is decreased in subjects with PD and healthy controls in response to LRRK2 kinase inhibition, showing promise as a biomarker of target engagement 18,31,32 . However, Rab10 phosphorylation does not correlate with LRRK2 levels or distinguish between PD patients and controls, limiting its utility as a patient enrichment biomarker 32,33 . This suggests a potential dissociation between LRRK2 activity and levels and further elucidation is needed to better understand the conditions in which LRRK2 phosphorylates Rab10 and how this may impact its use as a biomarker.…”

mentioning

confidence: 99%

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Mitochondrial DNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2 Parkinson’s disease

Gonzalez‐Hunt

Thacker

Toste

et al. 2020

Sci Rep

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Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson’s disease (PD) and LRRK2 kinase inhibitors are currently being tested in early phase clinical trials. In order to ensure the highest chance of success, a biomarker-guided entry into clinical trials is key. LRRK2 phosphorylation, and phosphorylation of the LRRK2 substrate Rab10, have been proposed as target engagement biomarkers for LRRK2 kinase inhibition. However, a pharmacodynamic biomarker to demonstrate that a biological response has occurred is lacking. We previously discovered that the LRRK2 G2019S mutation causes mitochondrial DNA (mtDNA) damage and is LRRK2 kinase activity-dependent. Here, we have explored the possibility that measurement of mtDNA damage is a “surrogate” for LRRK2 kinase activity and consequently of kinase inhibitor activity. Mitochondrial DNA damage was robustly increased in PD patient-derived immune cells with LRRK2 G2019S mutations as compared with controls. Following treatment with multiple classes of LRRK2 kinase inhibitors, a full reversal of mtDNA damage to healthy control levels was observed and correlated with measures of LRRK2 dephosphorylation. Taken together, assessment of mtDNA damage levels may be a sensitive measure of altered kinase activity and provide an extended profile of LRRK2 kinase modulation in clinical studies.

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Section: Rab8 and Rab10 Phosphorylation In Control And Lrrk2 G2019s Psupporting

confidence: 92%

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mitochondrial DNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2 Parkinson’s disease

Gonzalez‐Hunt

Thacker

Toste

et al. 2020

Sci Rep

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“…Alternatively, at sites with such capabilities, immortalization of lymphocytes might be a useful strategy to identify new biomarkers from one type of cell. For instance, we were able to detect centrosomal cohesion deficits in PBMC derived lymphoblastoid cell lines from LRRK2 G2019S Parkinson's disease patients, as well as in a subset of sporadic PD patients (Fernandez et al, 2019). This approach, however, is better suited for patient stratification purposes in clinical research studies, as compared to rapid and sensitive markers of target engagement required in a clinical trial.…”

Section: Measurement Of Lrrk2 In Blood and Blood Derivativesmentioning

confidence: 97%

The Current State-of-the Art of LRRK2-Based Biomarker Assay Development in Parkinson’s Disease

et al. 2020

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Evidence is mounting that LRRK2 function, particularly its kinase activity, is elevated in multiple forms of Parkinson's disease, both idiopathic as well as familial forms linked to mutations in the LRRK2 gene. However, sensitive quantitative markers of LRRK2 activation in clinical samples remain at the early stages of development. There are several measures of LRRK2 activity that could potentially be used in longitudinal studies of disease progression, as inclusion/exclusion criteria for clinical trials, to predict response to therapy, or as markers of target engagement. Among these are levels of LRRK2, phosphorylation of LRRK2 itself, either by other kinases or via auto-phosphorylation, its in vitro kinase activity, or phosphorylation of downstream substrates. This is advantageous on many levels, in that multiple indices of elevated kinase activity clearly strengthen the rationale for targeting this kinase with novel therapeutic candidates, and provide alternate markers of activation in certain tissues or biofluids for which specific measures are not detectable. However, this can also complicate interpretation of findings from different studies using disparate measures. In this review we discuss the current state of LRRK2-focused biomarkers, the advantages and disadvantages of the current pallet of outcome measures, the gaps that need to be addressed, and the priorities that the field has defined.

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Targeting Rab‐RILPL interactions as a strategy to downregulate pathogenic LRRK2 in Parkinson's disease

Alexander,

Naaldijk,

Fasiczka

et al. 2023

Journal of Peptide Science

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Familial Parkinson's disease (PD) is frequently linked to multiple disease‐causing mutations within Leucine‐Rich Repeat Protein Kinase 2 (LRRK2), leading to aberrant kinase activity. Multiple pathogenic effects of enhanced LRRK2 activity have been identified, including loss of cilia and centrosomal cohesion defects. When phosphorylated by LRRK2, Rab8a and Rab10 bind to phospho‐specific RILPL effector proteins. RILPL‐mediated accumulation of pRabs proximal to the mother centriole is critical for initiating deficits in ciliogenesis and centrosome cohesion mediated by LRRK2. We hypothesized that Rab‐derived phospho‐mimics may serve to block phosphorylated Rab proteins from docking with RILPL in the context of hyperactive LRRK2 mutants. This would serve as an alternative strategy to downregulate pathogenic signaling mediated by LRRK2, rather than targeting LRRK2 kinase activity itself. To test this theory, we designed a series of constrained peptides mimicking phosphorylated Switch II derived from Rab8. These RILPL interacting peptides, termed RIP, were further shown to permeate cells. Further, several peptides were found to bind RILPL2 and restore ciliogenesis and centrosomal cohesion defects in cells expressing PD‐associated mutant LRRK2. This research demonstrates the utility of constrained peptides as downstream inhibitors to target pathogenic LRRK2 activity and may provide an alternative approach to target specific pathways activated by LRRK2.

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Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients

Cited by 34 publications

References 43 publications

Mitochondrial DNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2 Parkinson’s disease

Mitochondrial DNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2 Parkinson’s disease

The Current State-of-the Art of LRRK2-Based Biomarker Assay Development in Parkinson’s Disease

Targeting Rab‐RILPL interactions as a strategy to downregulate pathogenic LRRK2 in Parkinson's disease

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