Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. ...It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann–Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) 2.85 μmol/l/h versus 3.12 μmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls), and when including the entire cohort (2.89 μmol/l/h versus 3.10 μmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 μmol/l/h versus 3.10 μmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31–0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.
•Activity was measured for 5 lysosomal enzymes in blood spots of PD and controls.•Alpha galactosidase A (deficient in Fabry disease) activity is reduced in PD cases.•Alpha galactosidase A and acid sphingomylinase are elevated in LRRK2 carriers.
Mutations in GBA and LRRK2 genes have been implicated in Parkinson disease (PD), particularly in Ashkenazi Jews.
An Israeli Ashkenazi cohort of 420 patients with PD, 333 elderly controls, and 3,805 ...young controls was screened for eight GBA mutations, which are associated with mild (N370S, R496H) and severe (84GG, IVS2 + 1, V394L, D409H, L444P, RecTL) Gaucher disease. Patients with PD and elderly controls were also genotyped for LRRK2 G2019S.
GBA carrier frequency was 17.9% in patients with PD compared to 4.2% in elderly and 6.35% in young controls. The proportion of severe mutation carriers among PD patient GBA carriers was 29% compared to 7% among young controls. Severe and mild GBA mutations increased the risk of developing PD by 13.6- and 2.2-fold, and affected the average age at PD onset (AAO), 55.7 and 57.9 years, compared to 60.7 years in patients without known GBA or LRRK2 mutations.
These data demonstrate genotype-phenotype correlations between different GBA mutations and Parkinson disease (PD) risk and AAO in Ashkenazi Jews. Additionally, an earlier AAO was observed in LRRK2 G2019S carrier PD patients. Finally, these data demonstrate that a surprisingly high frequency, more than one third of our patient population, carried a mutation in GBA or LRRK2.
Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to ...disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson’s Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson’s disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal–lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.
Biallelic GBA mutations cause Gaucher disease (GD), and heterozygous carriers are at risk for synucleinopathies. No founder GBA mutations in French‐Canadians are known. GBA was fully sequenced using ...targeted next generation and Sanger sequencing in French‐Canadian Parkinson disease (PD) patients (n = 436), rapid eye movement (REM)‐sleep behavior disorder (RBD) patients (n = 189) and controls (n = 891). Haplotype, identity‐by‐descent (IBD) and principal component analyses (PCA) were performed using single nucleotide polymorphism‐chip data. Data on GD patients from Toronto and Montreal were collected from patients' files. A GBA p.Trp378Gly mutation was identified in two RBD and four PD patients (1% of all patients combined), and not in controls. The two RBD patients had converted to DLB within 3 years of their diagnosis. Haplotype, IBD and PCA analysis demonstrated that this mutation is from a single founder. Out of 167 GD patients screened, 15 (9.0%) carried the p.Trp378Gly mutation, all in trans with p.Asn370Ser. Three (20%) of the GD patients with the p.Trp378Gly mutation had developed Parkinsonism, and 11 patients had family history of PD. The p.Trp378Gly mutation is the first French‐Canadian founder GBA mutation to be described, which leads to synucleinopathies and to GD type 1 when in compound heterozygosity with p.Asn370Ser.
A French‐Canadian founder mutation in GBA, p.Trp378Gly, is located between the enzyme active site and the binding area of Saposin C. This mutation causes Gaucher disease in compound heterozygous carriers, with or without Parkinson disease, and is a risk factor for synucleinopathies in heterozygous carriers.
We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare ...variant, a missense in SLC1A4 (c. 766G>A p. E256K), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. l‐Serine is essential for neuronal survival and differentiation. Indeed, l‐serine biosynthesis disorders affect brain development and cause severe ID. In the brain, l‐serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of l‐serine into neurons and the release of glia‐borne l‐serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of l‐serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID.
GBA
mutations are among the most common genetic risk factors for Parkinson disease (PD) worldwide. We aimed to identify genetic modifiers of the age at onset (AAO) in
GBA
-associated PD. The study ...included a genome-wide discovery phase, including a cohort of 79 patients with the
GBA
p.N370S mutation, and candidate validation and replication analyses of 8 SNPs in patients with mild (
n
= 113) and severe (
n
= 41)
GBA
mutations. Genotyping was performed using the Affymetrix human SNP 6.0 array and TaqMan assays. In the genome-wide phase, none of the SNPs passed the genome-wide significance threshold. Eight SNPs were selected for further analysis from the top hits. In all
GBA
-associated PD patients (
n
= 153), the
BIN1
rs13403026 minor allele was associated with an older AAO (12.4 ± 5.9 years later,
p
= 0.0001), compared to patients homozygous for the major allele. Furthermore, the AAO was 10.7 ± 6.8 years later in patients with mild
GBA
mutations, (
p
= 0.005, validation group), and 17.1 ± 2.5 years later in patients with severe
GBA
mutations (
p
= 0.01, replication). Our results suggest that alterations in the
BIN1
locus, previously associated with Alzheimer disease, may modify the AAO of
GBA
-associated PD. More studies in other populations are required to examine the role of
BIN1
-related variants in
GBA
-associated PD.
Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal condition for Parkinson’s disease (PD) and other synucleinopathies, which often occurs many years before the onset of PD. We ...analyzed 261 RBD patients and 379 controls for nine PD-associated SNPs and examined their effects, first upon on RBD risk and second, on eventual progression to synucleinopathies in a prospective follow-up in a subset of patients. The
SCARB2
rs6812193 (OR = 0.67, 95 % CI = 0.51–0.88,
p
= 0.004) and the
MAPT
rs12185268 (OR–0.43, 95 % CI–0.26–0.72,
p
= 0.001) were associated with RBD in different models. Kaplan-Meier survival analysis in a subset of RBD patients (
n
= 56), demonstrated that homozygous carriers of the
USP25
rs2823357 SNP had progressed to synucleinopathies faster than others (log-rank
p
= 0.003, Breslow
p
= 0.005, Tarone-Ware
p
= 0.004). As a proof-of-concept study, these results suggest that RBD may be associated with at least a subset of PD-associated genes, and demonstrate that combining genetic and prodromal clinical data may help identifying individuals that are either more or less susceptible to develop synucleinopathies. More studies are necessary to replicate these results, and identify more genetic factors affecting progression from RBD to synucleinopathies.
GBA
and
LRRK2
mutations increase susceptibility to Parkinson disease (PD), which is characterized by various disabling symptoms. An extended cohort of 600 Ashkenazi PD patients was screened for the
...LRRK2
G2019S and for eight
GBA
mutations. Reported initial symptoms were compared between three genotypic groups of patients: carriers of
GBA
mutations, carriers of
LRRK2
G2019S mutation, and non-carriers. More
LRRK2
G2019S carriers reported muscle stiffness (rigidity,
p
= 0.007) and balance disturbances (
p
= 0.008), while more
GBA
mutation carriers reported slowness (bradykinesia,
p
= 0.021). These results suggest distinct effects of
LRRK2
or
GBA
mutations on the initial symptoms of PD.
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