R1441G but not G201S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils

Fan, Yuxin; Nirujogi, Raja Sekhar; Garrido, Alícia; Martínez, Javier Rúiz; Bergareche-Yarza, Alberto; Rezola, Elisabet Mondragón; Aragón, Ana Vinagre; Croitoru, Ioana; Pagola, Ana Gorostidi; Markinez, Laura Paternain; Alcalay, Roy N.; Hickman, Richard A.; Duering, Jonas; Pratuseviciute, Neringa; Padmanabhan, Shalini; Valldeoriola, Francesc; Martı́, Marı́a José; Tolosa, Eduardo; Alessi, Dario R.; Sammler, Esther

doi:10.1101/2021.01.28.21249614

Cited by 4 publications

(4 citation statements)

References 33 publications

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“…LRRK2-dependent Rab10 phosphorylation at threonine 73, in peripheral blood as a biomarker for LRRK2 kinase activity. We have shown that LRRK2-dependent Rab10 phosphorylation is significantly elevated in human peripheral blood neutrophils derived from heterozygous LRRK2 R1441G mutation carriers with and without PD 10 – in keeping with the 3-4-fold activation of the LRRK2 kinase in cellular and knock-in animal models of LRRK2 R1441 hotspot mutations 3 20 21 . An even greater effect on LRRK2-dependent Rab10 phosphorylation is seen with the VPS35 D620N mutation that enhances LRRK2 kinase pathway activity in mice and human by a yet unknown mechanism 11 .…”

Section: Discussionsupporting

confidence: 68%

Elevated urine BMP phospholipids in LRRK2 and VPS35 mutation carriers with and without Parkinson’s disease

Gomes

Garrido

Tonelli

et al. 2022

Preprint

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Background: Parkinson's disease is the second most common neurodegenerative condition and has no cure. With the emergence of targeted treatments such as LRRK2 small molecule inhibitors that are currently being evaluated in clinical trials there is an urgent need for patient stratification and target engagement biomarkers. Urine BMP (didocohexaenoyl (22:6) bis(monoacylglycerol)phosphate) levels have previously been reported to be elevated in gain-of-kinase function LRRK2 G2019S mutation carriers and reduced in LRRK2 knockout mice, as well as non-human primates treated with LRRK2 kinase inhibitors. Objective: The purpose of this study was to independently validate and expand our understanding of urine BMPs as a PD biomarker in carriers of LRRK2 G2019S but also LRRK2 R1441 hotspot mutations, VPS35 D620N and GBA variants compared to idiopathic PD and control subjects. Methods: Up to 20 BMP species including total and 2,2'- isoforms of the di-18:1-BMP and di-22:6-BMP species were measured in urine from 106 participants: 22 controls, 31 with iPD, 10 with PD associated with GBA risk variants, as well as 18 LRRK2 G2019S, 13 LRRK2 R1441G/S and 10 VPS35 D620N mutation carriers either with or without PD. Results: Urine BMP levels were consistently elevated in carriers of LRRK2 G2019S and R1441G/C as well as VPS35 D620N mutations, but not those carrying GBA risk variants. Conclusion: Urine BMP levels are attractive and promising biomarkers for patient stratification in PD and potentially target engagement in clinical trials. Our results further highlight the convergence of the LRRK2 and VPS35 signalling pathways.

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Section: Discussionsupporting

confidence: 68%

Elevated urine BMP phospholipids in LRRK2 and VPS35 mutation carriers with and without Parkinson’s disease

Gomes

Garrido

Tonelli

et al. 2022

Preprint

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“…Other groups have measured pT73 Rab10 or phosphorylation stoichiometry in neutrophils, a subset of cells in peripheral blood that express both LRRK2 and Rab10, in patients with sporadic PD and LRRK2 G2019S carriers with and without PD. Results from these studies vary from no detectable increase in pT73 Rab10 to about twofold increase in pT73 Rab10 in LRRK2 G2019S carriers versus noncarriers (32)(33)(34)(35)(36).…”

Section: Lrrk2 Activity Is Increased In Patients With Sporadic Pd And...mentioning

confidence: 93%

“…The degree of elevation of Rab10 phosphorylation in peripheral immune cells or other tissue samples derived from carriers of these additional PD-causing LRRK2 variants beyond the G2019S mutation is not yet well defined. Preliminary data in cell lines, mouse tissues, and neutrophils from a limited number of LRRK2 R1441G carriers suggest that kinase activity for some point mutations is elevated by more than the twofold seen in LRRK2 G2019S carriers, supporting 50% or greater LRRK2 inhibition as a minimum target for therapeutic efficacy in clinical studies (5,33,37).…”

Section: Lrrk2 Activity Is Increased In Patients With Sporadic Pd And...mentioning

confidence: 99%

Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease

et al. 2022

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Mutations in leucine-rich repeat kinase 2 ( LRRK2 ) are the most common genetic risk factors for Parkinson’s disease (PD). Increased LRRK2 kinase activity is thought to impair lysosomal function and may contribute to the pathogenesis of PD. Thus, inhibition of LRRK2 is a potential disease-modifying therapeutic strategy for PD. DNL201 is an investigational, first-in-class, CNS-penetrant, selective, ATP-competitive, small-molecule LRRK2 kinase inhibitor. In preclinical models, DNL201 inhibited LRRK2 kinase activity as evidenced by reduced phosphorylation of both LRRK2 at serine-935 (pS935) and Rab10 at threonine-73 (pT73), a direct substrate of LRRK2. Inhibition of LRRK2 by DNL201 demonstrated improved lysosomal function in cellular models of disease, including primary mouse astrocytes and fibroblasts from patients with Gaucher disease. Chronic administration of DNL201 to cynomolgus macaques at pharmacologically relevant doses was not associated with adverse findings. In phase 1 and phase 1b clinical trials in 122 healthy volunteers and in 28 patients with PD, respectively, DNL201 at single and multiple doses inhibited LRRK2 and was well tolerated at doses demonstrating LRRK2 pathway engagement and alteration of downstream lysosomal biomarkers. Robust cerebrospinal fluid penetration of DNL201 was observed in both healthy volunteers and patients with PD. These data support the hypothesis that LRRK2 inhibition has the potential to correct lysosomal dysfunction in patients with PD at doses that are generally safe and well tolerated, warranting further clinical development of LRRK2 inhibitors as a therapeutic modality for PD.

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“…Therefore, expression or phosphorylation levels of LRRK2 and its Rab substrates have the potential to serve as biomarkers for PD due to increased LRRK2 activity (18). However, extensive studies in blood-derived cells employing distinct approaches to detect levels/phosphorylation of LRRK2 or Rab substrates have been relatively unsuccessful in differentiating LRRK2 mutation PD patients or idiopathic PD patients from healthy controls (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

A potential patient stratification biomarker for Parkinso’s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells

Naaldijk

Fernández

Fasiczka

et al. 2023

Preprint

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Parkinson's disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they acumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate PD patients who will benefit from LRRK2-related therapeutics.

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R1441G but not G201S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils

Cited by 4 publications

References 33 publications

Elevated urine BMP phospholipids in LRRK2 and VPS35 mutation carriers with and without Parkinson’s disease

Elevated urine BMP phospholipids in LRRK2 and VPS35 mutation carriers with and without Parkinson’s disease

Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease

A potential patient stratification biomarker for Parkinso’s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells

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