A Flat BAR Protein Promotes Actin Polymerization at the Base of Clathrin-Coated Pits.

Multiple proteins act co-operatively in mammalian clathrin-mediated endocytosis (CME) to generate endocytic vesicles from the plasma membrane. The principles controlling the activation and organization of the actin cytoskeleton during mammalian CME are, however, not fully understood. Here, we show that the protein FCHSD2 is a major activator of actin polymerization during CME. FCHSD2 deletion leads to decreased ligand uptake caused by slowed pit maturation. FCHSD2 is recruited to endocytic pits by the scaffold protein intersectin via an unusual SH3-SH3 interaction. Here, its flat F-BAR domain binds to the planar region of the plasma membrane surrounding the developing pit forming an annulus. When bound to the membrane, FCHSD2 activates actin polymerization by a mechanism that combines oligomerization and recruitment of N-WASP to PI(4,5)P2, thus promoting pit maturation. Our data therefore describe a molecular mechanism for linking spatiotemporally the plasma membrane to a force-generating actin platform guiding endocytic vesicle maturation.

Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.

BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease. METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391). FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention. INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services. FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.

The Lasting impact of the COVID-19 pandemic on outpatient neurology consultations.

Background: The COVID-19 pandemic prompted rapid changes in outpatient neurology services and there remain unanswered questions regarding its long-term impact. First, what are the lasting changes of the pandemic on demographics and outcomes of new referrals and patients reviewed at outpatient neurology clinics? Safety concerns about virtual consultations during the initial stages of the pandemic were also raised. Has the continual adoption of virtual consultations led to negative outcomes for patients? Methods: New referrals and first clinic appointments in 2019 (prepandemic baseline) and 2022 (postpandemic) in a tertiary referral centre were compared retrospectively. 7294 referrals (4946 clinic appointments) in 2019 and 6989 referrals (3976 clinic appointments) in 2022 were assessed. Outcomes investigated were rates of referrals accepted, time to clinic consultation, number of outpatient investigations per appointment, rates of discharge and the risk of reassessment. Results: There was a change in triaging practice postpandemic, with more patients being offered virtual assessments. Virtual appointments were offered to a specific suitable cohort of patients. This resulted in a faster time to consultation, fewer investigations, higher rates of discharge, with a reduced risk of reassessment compared with prepandemic patients, and patients postpandemic who were seen face to face. Conclusion: Outpatient neurology services have adapted postpandemic by effectively triaging referrals and allocating new patients appropriately to face-to-face or virtual clinics, improving patient outcomes and safety.

The Peripheral Inflammatory Response to Alpha-Synuclein and Endotoxin in Parkinson's Disease.

The immune system is activated in Parkinson's Disease (PD), as evidenced by neuroinflammatory changes within the brain as well as elevated immune markers in peripheral blood. Furthermore, inflammatory cytokine levels in the blood are associated with disease severity and rate of progression. However, the factors driving this immune response in PD are not well established. We investigated cell-extrinsic factors in systemic immune activation by using α-synuclein monomers and fibrils, as well as bacterial toxins, to stimulate peripheral blood mononuclear cells (PBMCs) derived from 31 patients and age/gender-matched controls. α-synuclein monomers or fibrils resulted in a robust cytokine response (as measured by supernatant cytokine concentrations and mRNA expression in cultured cells) in both PD and control PBMCs, similar to that induced by bacterial LPS. We found no PD vs. control differences in cytokine production, nor in mRNA expression. Levels of endotoxin within the recombinant α-synuclein used in these experiments were very low (0.2-1.3EU/mL), but nonetheless we found that comparable levels were sufficient to potentially confound our cytokine concentration measurements for a number of cytokines. However, α-synuclein monomers increased production of IL-1ß and IL-18 to levels significantly in excess of those induced by low-level endotoxin. In conclusion, this study: (i) highlights the importance of accounting for low-level endotoxin in antigen-PBMC stimulation experiments; (ii) indicates that cell-extrinsic factors may be a major contributor to immune activation in PD; and (iii) suggests that α-synuclein may play a role in inflammasome-related cytokine production in the periphery.