LRRK2 p.M1646T is associated with glucocerebrosidase activity and with Parkinson's disease

Sosero, Yuri L.; Yu, Eric; Krohn, Lynne; Rudakou, Uladzislau; Mufti, Kheireddin; Ruskey, Jennifer A.; Asayesh, Farnaz; Laurent, Sandra B.; Spiegelman, Dan; Fahn, Stanley; Waters, Cheryl; Sardi, S. Pablo; Bandrés‐Ciga, Sara; Alcalay, Roy N.; Gan‐Or, Ziv; Senkevich, Konstantin

doi:10.1016/j.neurobiolaging.2021.02.018

Cited by 16 publications

(19 citation statements)

References 31 publications

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“…Second, methodological differences in the assessment of GCase activity (i.e., cell based vs. in vitro) may capture different aspects of this interplay. A further study on blood samples from PD-patients identified a correlation between the LRRK2 variant M1646T and increased GCase activity 17 , consistent with the result we had obtained for LRRK2 G2019S carriers 14 .…”

Section: Introductionsupporting

confidence: 89%

LRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson’s disease

Kedariti

Frattini

Baden

et al. 2022

npj Parkinsons Dis.

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Leucine-rich repeat kinase 2 (LRRK2) is a kinase involved in different cellular functions, including autophagy, endolysosomal pathways, and immune function. 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 performed a comprehensive analysis of GCase levels and activity in complementary LRRK2 models, including (i) LRRK2 G2019S knock in (GSKI) mice, (ii) peripheral blood mononuclear cell (PBMCs), plasma, and fibroblasts from PD patients carrying LRRK2 G2019S mutation, (iii) patient iPSCs-derived neurons; (iv) endogenous and overexpressed cell models. In some of 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. GCase protein level is reduced in GSKI brain tissues and in G2019S iPSCs-derived neurons, but increased in fibroblasts and PBMCs from patients, suggesting cell-type-specific effects. Overall, our study indicates that LRRK2 kinase activity affects both the levels and the catalytic activity of GCase in a cell-type-specific manner, with important implications in the context of therapeutic application of LRRK2 inhibitors in GBA1-linked and idiopathic PD.

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Section: Introductionsupporting

confidence: 89%

LRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson’s disease

Kedariti

Frattini

Baden

et al. 2022

npj Parkinsons Dis.

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“…Both cohorts have been previously described in detail. 14 , 21 , 22 Rare variants analysis was performed in three cohorts sequenced at McGill University from Columbia University, McGill University (Quebec, Canada and Montpellier, France) and Sheba Medical Center ( Table 1 ). In addition, rare variants analysis was performed in the Accelerating Medicines Partnership-Parkinson Disease (AMP-PD) initiative cohorts ( https://amp-pd.org/ ).…”

Section: Methodsmentioning

confidence: 99%

GALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson’s disease

Senkevich

Zorca

Dworkind

et al. 2022

Brain

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The association between glucocerebrosidase (GCase), encoded by GBA, and Parkinson’s disease highlights the role of the lysosome in Parkinson’s disease pathogenesis. Genome-wide association studies (GWAS) in Parkinson’s disease have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase (GalCase), which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus, and if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with GalCase activity. We performed a GWAS in two independent cohorts from a)Columbia University and b)the Parkinson’s Progression Markers Initiative study, followed by a meta-analysis with a total of 976 Parkinson’s disease patients and 478 controls with available data on GalCase activity. We further analyzed the effects of common GALC variants on expression and GalCase activity using genomic colocalization methods. Mendelian randomization was used to study whether GalCase activity may be causal in Parkinson’s disease. To study the role of rare GALC variants we analyzed sequencing data from 5,028 Parkinson’s disease patients and 5,422 controls. Additionally, we studied the functional impact of GALC knock-out on alpha-synuclein accumulation and on GCase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered GalCase activity. The top hit in Parkinson's disease GWAS in the GALC locus, rs979812, is associated with increased GalCase activity (b = 1.2; se = 0.06; p = 5.10E-95). No other variants outside the GALC locus were associated with GalCase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased GalCase expression. Mendelian randomization suggested that increased GalCase activity may be causally associated with Parkinson’s disease (b = 0.025, se = 0.007, p = 0.0008). We did not find an association between rare GALC variants and Parkinson’s disease. GALC knockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced GalCase levels may be associated with Parkinson’s disease. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of GalCase affecting its activity. Our results nominate GALC as the gene associated with Parkinson’s disease in this locus and suggest that the association of variants in the GALC locus may be driven by their effect of increasing GalCase expression and activity. Whether altering GalCase activity could be considered as a therapeutic target should be further studied.

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“…The Columbia University cohort (New York) and the Parkinson’s Progression Markers Initiative (PPMI) cohort (detailed in Table 1). Both cohorts have been previously described in detail 14,21,22 . Rare variants analysis was performed in three cohorts sequenced at McGill university from Columbia University, McGill University (Quebec, Canada and Montpellier, France) and Sheba Medical Center (Table 1).…”

Section: Methodsmentioning

confidence: 99%

GALCvariants affect galactosylceramidase enzymatic activity and risk of Parkinson’s disease

Senkevich

Zorca

Dworkind

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

The association between glucocerebrosidase (GCase), encoded by GBA, and Parkinson's disease highlights the role of the lysosome in Parkinson's disease pathogenesis. Genome-wide association studies (GWAS) in Parkinson's disease have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase (GalCase), which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus, and if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with GalCase activity. We performed a GWAS in two independent cohorts from a)Columbia University and b)the Parkinson's Progression Markers Initiative study, followed by a meta-analysis with a total of 1,123 Parkinson's disease patients and 576 controls with available data on GalCase activity. We further analyzed the effects of common GALC variants on expression and GalCase activity using colocalization methods. Mendelian randomization was used to study whether GalCase activity may be causal in Parkinson's disease. To study the role of rare GALC variants we analyzed sequencing data from a total of 5,028 Parkinson's disease patients and 5,422 controls. Additionally, we studied the functional impact of GALC knock-out on alpha-synuclein accumulation and on GCase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered GalCase activity. The top hit in Parkinson's disease GWAS in the GALC locus, rs979812, is associated with increased GalCase activity (b=1.2; se=0.06; p=5.10E-95). No other variants outside the GALC locus were associated with GalCase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased GalCase expression. Mendelian randomization suggested that increased GalCase activity may be causally associated with Parkinson's disease (b=0.025, se=0.007, p=0.0008). We did not find an association between rare GALC variants and Parkinson's disease. GALC knockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced GalCase levels may be associated with Parkinson's disease. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of GalCase affecting its activity. Our results nominate GALC as the gene associated with Parkinson's disease in this locus and suggest that the association of variants in the GALC locus may be driven by their effect of increasing GalCase expression and activity. Whether altering GalCase activity could be considered as a therapeutic target should be further studied.

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LRRK2 p.M1646T is associated with glucocerebrosidase activity and with Parkinson's disease

Cited by 16 publications

References 31 publications

LRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson’s disease

LRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson’s disease

GALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson’s disease

GALCvariants affect galactosylceramidase enzymatic activity and risk of Parkinson’s disease

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