Glucocerebrosidase gene mutations are associated with Parkinson's disease in southern Italy

Recent studies have reported an association between the glucocerebrosidase (GBA) gene and Parkinson's disease (PD). To elucidate the role of this gene in our population, we screened 395 PD patients and 483 controls from southern Italy for the N370S and the L444P mutations. We found 11 patients (2.8%) carrying a heterozygous mutant GBA allele, whereas only one control subject (0.2%) had a heterozygous substitution (P = 0.0018). These results strongly suggest that Italian carriers of a GBA mutation have an increased risk of developing PD. © 2007 Movement Disorder Society     

Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course

Mutations in the glucocerebrosidase gene are associated with Parkinson's disease and Lewy body dementia. However, whether these alterations have any effect on the clinical course of Parkinson's disease is not clear. The glucocerebrosidase coding region was fully sequenced in 225 Parkinson's disease patients, 17 pathologically confirmed Lewy body dementia patients, and 186 controls from Spain. Twenty-two Parkinson's disease patients (9.8%) and 2 Lewy body dementia patients (11.8%) carried mutations in the glucocerebrosidase gene, compared with only 1 control (0.5%); P = .016 and P = .021 for Parkinson's disease and Lewy body dementia, respectively. The N370S and the L444P mutations represented 50% of the alterations. Two novel variants, L144V and S488T, and 7 previously described alterations were also found. Alterations in glucocerebrosidase were associated with a significant risk of dementia during the clinical course of Parkinson's disease (age at onset, years of evolution, and sex-adjusted odds ratio, 5.8; P = .001). Mutation carriers did not show worse motor symptoms, had good response to L-dopa, and tended to present the intermediate parkinsonian phenotype. Our findings suggest that mutations in the glucocerebrosidase gene not only increase the risk of both Parkinson's disease and Lewy body dementia but also strongly influence the course of Parkinson's disease with respect to the appearance of dementia.     

Glucocerebrosidase in Parkinson's disease: Insights into pathogenesis and prospects for treatment

PD involves several converging pathogenetic pathways to neurodegeneration; highlighted in specific cases by genetic mutations causing familial PD. Numerically, the most important genetic mutations associated with PD are those of the glucocerebrosidase gene. Approximately 10% of PD patients carry glucocerebrosidase mutations. This observation has enhanced focus on the autophagy‐lysosome system as important in pathogenesis. The relationship of the glucocerebrosidase pathway to the cause and progression of PD highlights the potential to use abnormalities identified as biomarkers and modify glucocerebrosidase activity or substrate accumulation as neuroprotection. Biomarkers relevant to the glucocerebrosidase pathway, for example, enzyme activity and substrate levels, may be identified in blood, urine, and CSF. These may be combined with clinical features to help identify mutation carriers that are at increased risk of PD. The molecular mechanisms by which glucocerebrosidase mutations may result in PD are not fully understood. There is evidence accumulating that there is a reciprocal interaction between glucocerebrosidase and alpha‐synuclein levels. This interaction may potentially be used to increase glucocerebrosidase enzyme activities and therefore reduce alpha‐synuclein levels to modify the course of PD. Substrate reduction therapy may be an alternative strategy, particularly if membrane abnormalities underlie the organellar dysfunction in PD neurodegeneration. © 2016 International Parkinson and Movement Disorder Society     

Gaucher disease ascertained through a Parkinson's center: Imaging and clinical characterization

Among the genes implicated for parkinsonism is glucocerebrosidase (GBA), which causes Gaucher disease (GD). Despite a growing literature that GD may present as parkinsonism, neuroimaging, olfaction, and neuropsychological testing have not been extensively reported. We describe transcranial sonography (TCS), 18F‐fluorodopa (F‐dopa) and fluorodeoxyglucose (FDG) Positron emission tomography, olfaction testing, neuropsychological testing, and clinical features in homozygous and compound heterozygous GBA mutation carriers identified through screening of 250 Ashkenazi Jewish parkinsonian individuals treated at a tertiary care center. We identified two individuals with N370S/R496H compound heterozygous mutations and two with N370S homozygous mutations; one individual died before completing detailed evaluation. TCS (n = 3) demonstrated nigral hyperechogenicity that was greater than controls [median area maximal substantia nigra echogenicity (aSNmax) = 0.28 cm² vs. 0.14 cm², P = 0.005], but similar to idiopathic PD (aSNmax = 0.31 cm²). FDG PET (n = 2) demonstrated hypermetabolism of the lentiform nuclei, and F‐fluorodopa PET (n = 2), bilateral reduction in striatal F‐dopa uptake. Olfaction was markedly impaired in the two tested cases, including onset of smell disturbance in adolescence in one. Neuropsychological features (n = 3) were consistent with Parkinson's disease (PD) or diffuse Lewy body disease (DLB). The imaging, neuropsychological and olfactory markers suggest the GD phenotype includes PD with and without features of DLB, marked olfactory loss, nigral hyperechogenicity on TCS, and F‐dopa and FDG PET abnormalities. © 2010 Movement Disorder Society     

LRRK2 R1628P variant is a risk factor of Parkinson's disease among Han‐Chinese from mainland China

Mutations in LRRK2, the gene that encodes leucine‐rich repeat kinase 2 (LRRK2), are associated with autosomal dominant and sporadic forms of Parkinson's disease (PD) and are the most common genetic causes of PD. Recently, a R1628P variant has been reported as a risk factor for PD in Taiwan and Singapore. To determine the association of this variant and PD in the Han‐Chinese population from mainland China, we analyzed its frequency in a cohort of 600 patients and 459 unrelated healthy controls. Forty (6.7%) patients were heterozygous and 3 (0.5%) homozygous for the R1628P variant, which was significantly more frequent than in the controls [2.4% heterozygous and 0.0% homozygous, Odds ratio = 3.14, 95%CI: 1.60–6.17, P < 0.01]. Considering the age at onset, this difference was found only in late‐onset PD (older than 50) [Odds ratio = 3.76, 95% CI: 1.90–7.45, P < 0.01]. Our data confirms that the LRRK2 R1628P variant is associated with an increased risk to develop late onset PD in the ethnic Han‐Chinese population. © 2009 Movement Disorder Society     

Evaluation of Strategies for Measuring Lysosomal Glucocerebrosidase Activity

Mutations in GBA1, which encode for the protein glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease and dementia with Lewy bodies. In addition, growing evidence now suggests that the loss of GCase activity is also involved in onset of all forms of Parkinson's disease, dementia with Lewy bodies, and other dementias, such as progranulin-linked frontal temporal dementia. As a result, there is significant interest in developing GCase-targeted therapies that have the potential to stop or slow progression of these diseases. Despite this interest in GCase as a therapeutic target, there is significant inconsistency in the methodology for measuring GCase enzymatic activity in disease-modeling systems and patient populations, which could hinder progress in developing GCase therapies. In this review, we discuss the different strategies that have been developed to assess GCase activity and highlight the specific strengths and weaknesses of these approaches as well as the gaps that remain. We also discuss the current and potential role of these different methodologies in preclinical and clinical development of GCase-targeted therapies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society     

Serum lipid alterations in GBA-associated Parkinson's disease

IntroductionMutations in the GBA gene, encoding for the lysosomal enzyme glucocerebrosidase, are associated with Gaucher disease. Alterations in plasma sphingolipids have been reported in Gaucher, and similarly in brain extracts in Lewy body disease. As GBA mutations are prevalent risk factors for Parkinson's disease and overlap of molecular pathways are presumable, here we assessed the lipid profiles in Parkinson's patients with and without GBA mutations.MethodsWe sequenced all GBA exons in 415 Parkinson's patients, previously genotyped for LRRK2. 64 patients (29 GBA positive vs. 35 non-GBA-carriers including 18 LRRK2 positive and 17 non-mutated) were analyzed for chitotriosidase activity and for the concentration of 40 lipid classes using HPLC-MS.Results29/415 patients (6.9%) carried 8 different GBA mutations associated with Gaucher or Parkinson's, including one novel mutation. Chitotriosidase activity was similar across the genetic groups, while the levels of key lipids were altered in GBA mutation carriers: Monohexosylceramide, Ceramide and Sphingomyelin were elevated; while Phosphatidic acid (PA), Phosphatidylethanolamine (PE), Plasmalogen phosphatidylethanolamine (PEp) and Acyl Phosphatidylglycerol (AcylPG) were decreased.ConclusionThe results suggest an important role for these lipids in GBA mediated Parkinson's disease and assist in the identification of common pathways between Gaucher and Parkinson's. Ultimately, our findings may lead to the identification of novel biomarkers for individuals at increased risk of developing Parkinson's disease.     

Elevated homocysteine levels in levodopa‐treated idiopathic Parkinson's disease: a meta‐analysis

To assess the association between the elevation of plasma homocysteine (Hcy) level and long‐term levodopa (L‐dopa) therapy in idiopathic Parkinson's disease (PD). We performed a systematic literature review to recruit original studies published up to May 14, 2012. Studies enrolled should be controlled, with specific information of long‐term L‐dopa application and plasma Hcy in patients with PD. Effects were summarized using standardized mean differences (SMDs) or weighted mean differences (WMDs). Our search enrolled 22 eligible studies. Plasma Hcy levels were significantly higher in L‐dopa‐treated patients than those in healthy controls [SMD 0.97; 95% confidence interval (CI) 0.80–1.14, P < 0.001], L‐dopa‐naïve patients with PD (SMD 0.99; 95% CI 0.54–1.44, P < 0.001), and untreated patients (SMD 0.52; 95% CI 0.18–0.86, P < 0.01). However, its levels in untreated patients with PD were not significantly higher than in healthy controls (SMD 0.24; 95% CI ?0.03 to 0.51, P > 0.05). Patients with PD treated with L‐dopa plus catechol‐O‐methyltransferase inhibitor (COMT‐I) showed lower plasma Hcy concentrations compared with L‐dopa‐treated patients (WMD 4.62; 95% CI 2.89–6.35, P < 0.001). L‐dopa treatment is associated with the increase in plasma Hcy level in patients with PD. COMT‐I may attenuate L‐dopa‐induced elevation of Hcy level.