Phenotypic effect of GBA1 variants in individuals with and without Parkinson's disease: The RAPSODI study.

BACKGROUND: Variants in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD). They are also risk factors for Parkinson's disease (PD), and modify the expression of the PD phenotype. The penetrance of GBA1 variants in PD is incomplete, and the ability to determine who among GBA1 variant carriers are at higher risk of developing PD, would represent an advantage for prognostic and trial design purposes. OBJECTIVES: To compare the motor and non-motor phenotype of GBA1 carriers and non-carriers. METHODS: We present the cross-sectional results of the baseline assessment from the RAPSODI study, an online assessment tool for PD patients and GBA1 variant carriers. The assessment includes clinically validated questionnaires, a tap-test, the University of Pennsyllvania Smell Identification Test and cognitive tests. Additional, homogeneous data from the PREDICT-PD cohort were included. RESULTS: A total of 379 participants completed all parts of the RAPSODI assessment (89 GBA1-negative controls, 169 GBA1-negative PD, 47 GBA1-positive PD, 47 non-affected GBA1 carriers, 27 GD). Eighty-six participants were recruited through PREDICT-PD (43 non-affected GBA1 carriers and 43 GBA1-negative controls). GBA1-positive PD patients showed worse performance in visual cognitive tasks and olfaction compared to GBA1-negative PD patients. No differences were detected between non-affected GBA1 carriers carriers and GBA1-negative controls. No phenotypic differences were observed between any of the non-PD groups. CONCLUSIONS: Our results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. However, we did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers.

α-Synuclein expression in response to bacterial ligands and metabolites in gut enteroendocrine cells: an in vitro proof of concept study.

Caudo-rostral migration of pathological forms of α-synuclein from the gut to the brain is proposed as an early feature in Parkinson's disease pathogenesis, but the underlying mechanisms remain unknown. Intestinal epithelial enteroendocrine cells sense and respond to numerous luminal signals, including bacterial factors, and transmit this information to the brain via the enteric nervous system and vagus nerve. There is evidence that gut bacteria composition and their metabolites change in Parkinson's disease patients, and these alterations can trigger α-synuclein pathology in animal models of the disorder. Here, we investigated the effect of toll-like receptor and free fatty acid receptor agonists on the intracellular level of α-synuclein and its release using mouse secretin tumour cell line 1 enteroendocrine cells. Secretin tumour cell line 1 enteroendocrine cells were treated for 24 or 48 h with toll-like receptor agonists (toll-like receptor 4 selective lipopolysaccharide; toll-like receptor 2 selective Pam3CysSerLys4) and the free fatty acid receptor 2/3 agonists butyrate, propionate and acetate. The effect of selective receptor antagonists on the agonists' effects after 24 hours was also investigated. The level of α-synuclein protein was measured in cell lysates and cell culture media by western blot and enzyme-linked immunosorbent assay. The level of α-synuclein and tumour necrosis factor messenger RNA was measured by quantitative reverse transcription real-time polymerase chain reaction. Stimulation of secretin tumour cell line 1 enteroendocrine cells for 24 and 48 hours with toll-like receptor and free fatty acid receptor agonists significantly increased the amount of intracellular α-synuclein and the release of α-synuclein from the cells into the culture medium. Both effects were significantly reduced by antagonists selective for each receptor. Toll-like receptor and free fatty acid receptor agonists also significantly increased tumour necrosis factor transcription, and this was effectively inhibited by corresponding antagonists. Elevated intracellular α-synuclein increases the likelihood of aggregation and conversion to toxic forms. Factors derived from bacteria induce α-synuclein accumulation in secretin tumour cell line 1 enteroendocrine cells. Here, we provide support for a mechanism by which exposure of enteroendocrine cells to specific bacterial factors found in Parkinson's disease gut dysbiosis might facilitate accumulation of α-synuclein pathology in the gut.

Evaluation of an Adapted Semi-Automated DNA Extraction for Human Salivary Shotgun Metagenomics.

Recent attention has highlighted the importance of oral microbiota in human health and disease, e.g., in Parkinson's disease, notably using shotgun metagenomics. One key aspect for efficient shotgun metagenomic analysis relies on optimal microbial sampling and DNA extraction, generally implementing commercial solutions developed to improve sample collection and preservation, and provide high DNA quality and quantity for downstream analysis. As metagenomic studies are today performed on a large number of samples, the next evolution to increase study throughput is with DNA extraction automation. In this study, we proposed a semi-automated DNA extraction protocol for human salivary samples collected with a commercial kit, and compared the outcomes with the DNA extraction recommended by the manufacturer. While similar DNA yields were observed between the protocols, our semi-automated DNA protocol generated significantly higher DNA fragment sizes. Moreover, we showed that the oral microbiome composition was equivalent between DNA extraction methods, even at the species level. This study demonstrates that our semi-automated protocol is suitable for shotgun metagenomic analysis, while allowing for improved sample treatment logistics with reduced technical variability and without compromising the structure of the oral microbiome.

Comprehensive short and long read sequencing analysis for the Gaucher and Parkinson's disease-associated GBA gene.

GBA variants carriers are at increased risk of Parkinson's disease (PD) and Lewy body dementia (LBD). The presence of pseudogene GBAP1 predisposes to structural variants, complicating genetic analysis. We present two methods to resolve recombinant alleles and other variants in GBA: Gauchian, a tool for short-read, whole-genome sequencing data analysis, and Oxford Nanopore sequencing after PCR enrichment. Both methods were concordant for 42 samples carrying a range of recombinants and GBAP1-related mutations, and Gauchian outperformed the GATK Best Practices pipeline. Applying Gauchian to sequencing of over 10,000 individuals shows that copy number variants (CNVs) spanning GBAP1 are relatively common in Africans. CNV frequencies in PD and LBD are similar to controls. Gains may coexist with other mutations in patients, and a modifying effect cannot be excluded. Gauchian detects more GBA variants in LBD than PD, especially severe ones. These findings highlight the importance of accurate GBA analysis in these patients.

The remote assessment of parkinsonism supporting the ongoing development of interventions in Gaucher disease.

Mutations in GBA which are causative of Gaucher disease in their biallelic form, are the most common genetic risk factor for Parkinson's disease (PD). The diagnosis of PD relies upon clinically defined motor features which appear after irreversible neurodegeneration. Prodromal symptoms of PD may provide a means to predict latent pathology, years before the onset of motor features. Previous work has reported prodromal features of PD in GBA mutation carriers, however this has been insufficiently sensitive to identify those that will develop PD. The Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease (RAPSODI GD) study assesses a large cohort of GBA mutation carriers, to aid development of procedures for earlier diagnosis of PD.

Lay abstract Changes in a gene called GBA cause a rare condition called Gaucher disease and are the most common genetic risk factor for Parkinson's disease (PD). To diagnose PD, patients must show symptoms of disordered movement which only occur after irreversible brain cell loss. Earlier symptoms may allow for the prediction of PD, years before movement symptoms occur. Previous work has reported earlier symptoms of PD occurring in people with GBA changes, however these studies have not been able to identify those at risk of developing PD. The Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease (RAPSODI GD) study assesses a large group of people with GBA changes, to help develop a way to diagnose PD earlier.

Intronic Haplotypes in the GBA Gene Do Not Predict Age at Diagnosis of Parkinson's Disease.

BACKGROUND: GBA mutations are a common risk factor for Parkinson's disease (PD). A recent study has suggested that GBA haplotypes, identified by intronic variants, can affect age at diagnosis of PD. OBJECTIVES: In this study, we assess this hypothesis using long reads across a large cohort and the publicly available Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) cohort. METHODS: We recruited a PD cohort through the Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease study (RAPSODI) and sequenced GBA using Oxford Nanopore technology. Genetic and clinical data on the full AMP-PD cohort were obtained from the online portal of the consortium. RESULTS: A total of 1417 participants were analyzed. There was no significant difference in age at PD diagnosis between the two main haplotypes of the GBA gene. CONCLUSIONS: GBA haplotypes do not affect age at diagnosis of PD in the two independent cohorts studied. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Understanding how minds vary relates to skill in inferring mental states, personality, and intelligence.

Using a "theory of mind" allows us to explain and predict others' behavior in terms of their mental states, yet individual differences in the accuracy of mental state inferences are not well understood. We hypothesized that the accuracy of mental state inferences can be explained by the ability to characterize the mind giving rise to the mental state. Under this proposal, individuals differentiate between minds by representing them in "Mind-space"-a multidimensional space where dimensions reflect any characteristic of minds that allows them to be individuated. Individual differences in the representation of minds and the accuracy of mental state inferences are explained by one's model of how minds can vary (Mind-space) and ability to locate an individual mind within this space. We measured the accuracy of participants' model of the covariance between dimensions in Mind-space that represent personality traits, and we found this was associated with the accuracy of mental state inference (Experiment 1). Mind-space accuracy also predicted the ability to locate others within Mind-space on dimensions of personality and intelligence (Experiment 2). Direct evidence for the representation of minds in mental state inference was obtained by showing that the location of others in Mind-space affects the probability of particular mental states being ascribed to them (Experiment 3). This latter effect extended to mental states dependent upon representation of trait covariation (Experiment 4). Results support the claim that mental state inference varies according to location in Mind-space, and therefore that adopting the Mind-space framework can explain some of the individual differences in theory of mind. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Quantifying compliance and acceptance through public and private social conformity.

Social conformity is a class of social influence whereby exposure to the attitudes and beliefs of a group causes an individual to alter their own attitudes and beliefs towards those of the group. Compliance and acceptance are varieties of social influence distinguished on the basis of the attitude change brought about. Compliance involves public, but not private conformity, while acceptance occurs when group norms are internalised and conformity is demonstrated both in public and in private. Most contemporary paradigms measuring conformity conflate compliance and acceptance, while the few studies to have addressed this issue have done so using between-subjects designs, decreasing their sensitivity. Here we present a novel task which measures compliance and acceptance on a within-subjects basis. Data from a small sample reveal that compliance and acceptance can co-occur, that compliance is increased with an increasing majority, and demonstrate the usefulness of the task for future studies of conformity.