Evolution and clustering of prodromal parkinsonian features in GBA1 carriers.

BACKGROUND: Five to 25% of patients with PD carry glucocerebrosidase gene mutations, and 10% to 30% of glucocerebrosidase carriers will develop PD by age 80. Stratification of PD risk in glucocerebrosidase carriers provides an opportunity to target disease-modifying therapies. OBJECTIVE: Cross-sectional and longitudinal survey of prodromal PD signs among glucocerebrosidase carriers. DESIGN: Prospective assessment of 82 glucocerebrosidase mutation carriers and 35 controls over 4 to 5 years for prodromal clinical PD features. RESULTS: At all time points, olfactory (measured using University of Pennsylvania Smell Identification Test) and cognitive (Montreal Cognitive Assessment) function and the International Parkinson and Movement Disorder Society UPDRS parts II and III scores were significantly worse amongst glucocerebrosidase mutation carriers. Progression to microsmia (odds ratio: 8.5; 95% confidence interval: 2.6-28.2; P < 0.05) and mild cognitive impairment (odds ratio: 4.2; 95% confidence interval: 1.1-16.6; P < 0.05) were more rapid compared to controls. Those with worse olfaction also had worse cognition (OR, 1.5; 95% CI: 0.0-2.8; P < 0.05) and depression (OR, 1.3; 95% CI: 0.6-2.8; P < 0.05). No participants reached the MDS prodromal PD diagnostic criteria before PD diagnosis. One participant developed PD. He did not fulfill the International Parkinson and Movement Disorder Society prodromal PD criteria before diagnosis. CONCLUSION: Assessment of individual and clustered PD prodromal features may serve as a useful tool to identify high-risk subjects for conversion to PD. As a result of the low conversion rate in our glucocerebrosidase mutation carriers to date, prospective validation is needed in larger cohorts to establish the profile of these features in PD convertors. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers.

Numerically the most important risk factor for the development of Parkinson's disease (PD) is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase) activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD. Cells showed reduced GCase protein and activity, impaired macroautophagy, and increased α-synuclein levels. Advantages of this approach include easy access to stem cells, no requirement to reprogram, and retention of the intact host genome. Treatment with a GCase chaperone increased GCase protein levels and activity, rescued the autophagic defects, and decreased α-synuclein levels. These results provide the basis for further investigation of GCase chaperones or similar drugs to slow the progression of PD.

Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models.

GBA gene mutations are the greatest cause of Parkinson disease (PD). GBA encodes the lysosomal enzyme glucocerebrosidase (GCase) but the mechanisms by which loss of GCase contributes to PD remain unclear. Inhibition of autophagy and the generation of endoplasmic reticulum (ER) stress are both implicated. Mutant GCase can unfold in the ER and be degraded via the unfolded protein response, activating ER stress and reducing lysosomal GCase. Small molecule chaperones that cross the blood brain barrier help mutant GCase refold and traffic correctly to lysosomes are putative treatments for PD. We treated fibroblast cells from PD patients with heterozygous GBA mutations and Drosophila expressing human wild-type, N370S and L444P GBA with the molecular chaperones ambroxol and isofagomine. Both chaperones increased GCase levels and activity, but also GBA mRNA, in control and mutant GBA fibroblasts. Expression of mutated GBA in Drosophila resulted in dopaminergic neuronal loss, a progressive locomotor defect, abnormal aggregates in the ER and increased levels of the ER stress reporter Xbp1-EGFP. Treatment with both chaperones lowered ER stress and prevented the loss of motor function, providing proof of principle that small molecule chaperones can reverse mutant GBA-mediated ER stress in vivo and might prove effective for treating PD.

Endoplasmic reticulum and lysosomal Ca²âº stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts.

Mutations in ß-glucocerebrosidase (encoded by GBA1) cause Gaucher disease (GD), a lysosomal storage disorder, and increase the risk of developing Parkinson disease (PD). The pathogenetic relationship between the two disorders is unclear. Here, we characterised Ca(2+) release in fibroblasts from type I GD and PD patients together with age-matched, asymptomatic carriers, all with the common N370S mutation in ß-glucocerebrosidase. We show that endoplasmic reticulum (ER) Ca(2+) release was potentiated in GD and PD patient fibroblasts but not in cells from asymptomatic carriers. ER Ca(2+) signalling was also potentiated in fibroblasts from aged healthy subjects relative to younger individuals but not further increased in aged PD patient cells. Chemical or molecular inhibition of ß-glucocerebrosidase in fibroblasts and a neuronal cell line did not affect ER Ca(2+) signalling suggesting defects are independent of enzymatic activity loss. Conversely, lysosomal Ca(2+) store content was reduced in PD fibroblasts and associated with age-dependent alterations in lysosomal morphology. Accelerated remodelling of Ca(2+) stores by pathogenic GBA1 mutations may therefore feature in PD.

Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort.

IMPORTANCE: Numerically, the most important genetic risk factor for the development of Parkinson disease (PD) is the presence of a glucocerebrosidase gene (GBA) mutation. OBJECTIVE: To evaluate longitudinally and clinically a GBA mutation-positive cohort and the evolution of the prodromal features of PD. DESIGN, SETTING, AND PARTICIPANTS: Participants in a study of the etiology and prodrome of PD were reevaluated in this clinic-based 2-year follow-up report. Patients with type 1 Gaucher disease (GD) and heterozygous GBA mutation carriers were recruited in 2010 from the Lysosomal Storage Disorder Unit at the Royal Free Hospital, London, England. Thirty patients who previously received a diagnosis of type 1 GD, 28 heterozygous GBA mutation carriers, and 26 genetically unrelated controls were included. Exclusion criteria included a diagnosis of PD or dementia for both the patients with GD and the GBA mutation carriers and any existing neurological disease for the controls. MAIN OUTCOMES AND MEASURES: Assessment was performed for clinical markers using standardized scales for hyposmia, rapid eye movement sleep behavior disorder, depression, autonomic dysfunction, cognitive function, and parkinsonian motor signs (using the Unified Parkinson's Disease Rating Scale motor subscale [UPDRS part III]). RESULTS: Over 2 years, depression scores were significantly worse for heterozygous carriers (mean baseline, 0.65; mean follow-up, 2.88; P = .01), rapid eye movement sleep behavior disorder scores were significantly worse for patients with GD (mean baseline, 0.93; mean follow-up, 2.93; P < .001) and heterozygotes (mean baseline, 0.10; mean follow-up, 2.30; P < .001), and UPDRS part III scores were significantly worse for patients with GD (mean baseline, 4.29; mean follow-up, 7.82; P < .001) and heterozygotes (mean baseline, 1.97; mean follow-up, 4.50; P < .001). For controls, there was a small but significant deterioration in the UPDRS part II (activities of daily living) score (mean baseline, 0.00; mean follow-up, 0.58; P = .006). At 2 years, olfactory and cognitive assessment scores were lower in patients with GD and heterozygotes compared with controls, but they did not differ significantly from baseline. When the results from the patients with GD and the heterozygotes were combined, a significant deterioration from baseline was observed, as reflected in the Rapid Eye Movement Sleep Behaviour Disorder Questionnaire (mean baseline, 0.51; mean follow-up, 2.63; P < .001), Beck Depression Inventory (mean baseline, 1.72; mean follow-up, 4.44; P = .002), and UPDRS part II (mean baseline, 0.88; mean follow-up, 2.01; P < .001) and part III scores (mean baseline, 3.09; mean follow-up, 6.10; P < .001) (all P < .01), and at 2 years, significant differences in University of Pennsylvania Smell Identification Test, Unified Multiple System Atrophy Rating Scale, Mini-Mental State Examination, Montreal Cognitive Assessment, and UPDRS part II and part III scores were observed between patients with GD/heterozygotes and controls (all P < .05). CONCLUSIONS AND RELEVANCE: This study indicates that, as a group, GBA mutation-positive individuals show a deterioration in clinical markers consistent with the prodrome of PD. Within this group of individual, 10% appear to be evolving at a more rapid rate.

Visual short-term memory deficits associated with GBA mutation and Parkinson's disease.

Individuals with mutation in the lysosomal enzyme glucocerebrosidase (GBA) gene are at significantly high risk of developing Parkinson's disease with cognitive deficit. We examined whether visual short-term memory impairments, long associated with patients with Parkinson's disease, are also present in GBA-positive individuals-both with and without Parkinson's disease. Precision of visual working memory was measured using a serial order task in which participants observed four bars, each of a different colour and orientation, presented sequentially at screen centre. Afterwards, they were asked to adjust a coloured probe bar's orientation to match the orientation of the bar of the same colour in the sequence. An additional attentional 'filtering' condition tested patients' ability to selectively encode one of the four bars while ignoring the others. A sensorimotor task using the same stimuli controlled for perceptual and motor factors. There was a significant deficit in memory precision in GBA-positive individuals-with or without Parkinson's disease-as well as GBA-negative patients with Parkinson's disease, compared to healthy controls. Worst recall was observed in GBA-positive cases with Parkinson's disease. Although all groups were impaired in visual short-term memory, there was a double dissociation between sources of error associated with GBA mutation and Parkinson's disease. The deficit observed in GBA-positive individuals, regardless of whether they had Parkinson's disease, was explained by a systematic increase in interference from features of other items in memory: misbinding errors. In contrast, impairments in patients with Parkinson's disease, regardless of GBA status, was explained by increased random responses. Individuals who were GBA-positive and also had Parkinson's disease suffered from both types of error, demonstrating the worst performance. These findings provide evidence for dissociable signature deficits within the domain of visual short-term memory associated with GBA mutation and with Parkinson's disease. Identification of the specific pattern of cognitive impairment in GBA mutation versus Parkinson's disease is potentially important as it might help to identify individuals at risk of developing Parkinson's disease.

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease.

Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease with a lifetime risk in the UK population of almost 5%. An association between PD and Gaucher disease (GD) derived from the observation that GD patients and their heterozygous carrier relatives were at increased risk of PD. GD is an autosomal recessive lysosomal storage disorder caused by homozygous mutations in the gene encoding glucocerebrosidase (GBA). Approximately 5%-10% of PD patients have GBA mutations, making these mutations numerically the most important genetic predisposing risk factor for the development of PD identified to date. GBA mutations result in a phenotype that is virtually indistinguishable clinically, pharmacologically, and pathologically from sporadic PD, except GBA mutations result in a slightly earlier age of onset and more frequent cognitive impairment among PD patients. The mechanisms by which GBA mutations result in PD are not yet understood. Both reduced glucocerebrosidase enzyme (GCase) activity with lysosomal dysfunction, and unfolded protein response (UPR) with endoplasmic reticulum-associated degradation (ERAD) and stress are considered contributory.