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

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

A discursive approach to narrative accounts of hearing voices and recovery

Substantive objective: To research the range of discursive constructions ‘recovered’ voice hearers employ to describe hearing voices and the implications for positioning and subjectivity (what can be thought and felt) using each construction. Methodological objective and method: To explore a ‘sympathetic’ application of Foucauldian discourse analysis, adapting Willig’s (2008 Willig, C. 2008. Introducing Qualitative Research in Psychology, Maidenhead: Open University Press. ) method, analysing two published accounts. Results and conclusions: Heterogeneous discursive constructions for talking about hearing voices were identified, including: ‘many-’selves’’, ‘taking-the-lead-in-your-own-recovery’, ‘voices-as-an-’imagined-world’’ and ‘voices-as-a-coping-strategy-for-dealing-with-trauma’. The discourse of the biomedical model was not prominent, suggesting alternate discursive constructions may create subjects with a greater capacity for ‘living with voices’ and create a subjectivity from which vantage point the experience holds meaning and value and can be integrated into life experiences. This research may have useful clinical applications for mental health services aiming to collaboratively explore service users’ ways of understanding hearing voices

The Unmet Need for Interpreting Provision in UK Primary Care

Background: With increasing globalisation, the challenges of providing accessible and safe healthcare to all are great. Studies show that there are substantial numbers of people who are not fluent in English to a level where they can make best use of health services. We examined how health professionals manage language barriers in a consultation.Methods and Findings: This was a cross-sectional study in 41 UK general practices. Health professionals completed a proforma for a randomly allocated consultation session. Seventy-seven (63%) practitioners responded, from 41(59%) practices. From 1008 consultations, 555 involved patients who did not have English as a first language; 710 took place in English; 222 were in other languages, the practitioner either communicating with the patient in their own language/using an alternative language. Seven consultations were in a mixture of English/patient's own language. Patients' first languages numbered 37 (apart from English), in contrast to health practitioners, who declared at least a basic level of proficiency in 22 languages other than English. The practitioner's reported proficiency in the language used was at a basic level in 24 consultations, whereas in 21, they reported having no proficiency at all. In 57 consultations, a relative/friend interpreted and in 6, a bilingual member of staff/community worker was used. Only in 6 cases was a professional interpreter booked. The main limitation was that only one random session was selected and assessment of patient/professional fluency in English was subjective.Conclusions: It would appear that professional interpreters are under-used in relation to the need for them, with bilingual staff/family and friends being used commonly. In many cases where the patient spoke little/no English, the practitioner consulted in the patient's language but this approach was also used where reported practitioner proficiency was low. Further research in different setting is needed to substantiate these findings

Hagfish genome elucidates vertebrate whole-genome duplication events and their evolutionary consequences.

Polyploidy or whole-genome duplication (WGD) is a major event that drastically reshapes genome architecture and is often assumed to be causally associated with organismal innovations and radiations. The 2R hypothesis suggests that two WGD events (1R and 2R) occurred during early vertebrate evolution. However, the timing of the 2R event relative to the divergence of gnathostomes (jawed vertebrates) and cyclostomes (jawless hagfishes and lampreys) is unresolved and whether these WGD events underlie vertebrate phenotypic diversification remains elusive. Here we present the genome of the inshore hagfish, Eptatretus burgeri. Through comparative analysis with lamprey and gnathostome genomes, we reconstruct the early events in cyclostome genome evolution, leveraging insights into the ancestral vertebrate genome. Genome-wide synteny and phylogenetic analyses support a scenario in which 1R occurred in the vertebrate stem-lineage during the early Cambrian, and 2R occurred in the gnathostome stem-lineage, maximally in the late Cambrian-earliest Ordovician, after its divergence from cyclostomes. We find that the genome of stem-cyclostomes experienced an additional independent genome triplication. Functional genomic and morphospace analyses demonstrate that WGD events generally contribute to developmental evolution with similar changes in the regulatory genome of both vertebrate groups. However, appreciable morphological diversification occurred only in the gnathostome but not in the cyclostome lineage, calling into question the general expectation that WGDs lead to leaps of bodyplan complexity