Therapeutic Targeting of Proteostasis in Amyotrophic Lateral Sclerosis—a Systematic Review and Meta-Analysis of Preclinical Research

Funding This work was supported by AMS: 210JMG 3102 R45620 and CSO and MNDS: 217ARF R45951. Medical Research Council (MRC UK; MR/L016400/1).Peer reviewedPublisher PD

Sla1p serves as the targeting signal recognition factor for NPFX(1,2)D-mediated endocytosis

Efficient endocytosis requires cytoplasmic domain targeting signals that specify incorporation of cargo into endocytic vesicles. Adaptor proteins play a central role in cargo collection by linking targeting signals to the endocytic machinery. We have characterized NPFX(1,2) (NPFX[1,2]D) targeting signals and identified the actin-associated protein Sla1p as the adaptor for NPFX(1,2)D-mediated endocytosis in Saccharomyces cerevisiae. 11 amino acids encompassing an NPFX(1,2)D sequence were sufficient to direct uptake of a truncated form of the pheromone receptor Ste2p. In this context, endocytic targeting activity was not sustained by conservative substitutions of the phenylalanine or aspartate. An NPFX1,2D-related sequence was identified in native Ste2p that functions redundantly with ubiquitin-based endocytic signals. A two-hybrid interaction screen for NPFX(1,2)D-interacting proteins yielded SLA1, but no genes encoding Eps15 homology (EH) domains, protein modules known to recognize NPF peptides. Furthermore, EH domains did not recognize an NPFX(1,2)D signal when directly tested by two-hybrid analysis. SLA1 disruption severely inhibited NPFX(1,2)D-mediated endocytosis, but only marginally affected ubiquitin-directed uptake. NPFX(1,2)D-dependent internalization required a conserved domain of Sla1p, SLA1 homology domain, which selectively bound an NPFX(1,2)D-containing fusion protein in vitro. Thus, through a novel NPF-binding domain, Sla1p serves as an endocytic targeting signal adaptor, providing a means to couple cargo with clathrin- and actin-based endocytic machineries

Neuronal clusterin expression is associated with cognitive protection in amyotrophic lateral sclerosis

Research Funding Medical Research Council. Grant Number: MR/L016400/1 Academy of Medical Sciences. Grant Number: 210JMG 3102 R45620 MND Scotland Motor Neurone Disease Association Amyotrophic Lateral Sclerosis AssociationPeer reviewedPublisher PD

NLRP3 inflammasome as a key molecular target underlying cognitive resilience in amyotrophic lateral sclerosis

Funding Pathological Society of Great Britain and Ireland. Grant Number: Jean Shanks Foundation Clinical Lecturer Support G OR is funded by a Wellcome Trust PhD fellowship (108890/Z/15/Z). JMG is funded by a starter grant for clinical lecturers from the AMS (210JMG 3102 R45620) and a Clinical Lecturer Support Grant from The Pathological Society/Jean Shanks Foundation, and brain bank funding from the MRC (MR/L016400/1). EE is funded by a PhD fellowship from the CSO and MND Scotland: 217ARF R45951.Peer reviewedPublisher PD

Could an Impairment in Local Translation of mRNAs in Glia be Contributing to Pathogenesis in ALS?

One of the key pathways implicated in amyotrophic lateral sclerosis (ALS) pathogenesis is abnormal RNA processing. Studies to date have focussed on defects in RNA stability, splicing, and translation, but this review article will focus on the largely overlooked RNA processing mechanism of RNA trafficking, with particular emphasis on the importance of glia. In the central nervous system (CNS), oligodendrocytes can extend processes to myelinate and metabolically support up to 50 axons and astrocytes can extend processes to cover up to 100,000 synapses, all with differing local functional requirements. Furthermore, many of the proteins required in these processes are large, aggregation-prone proteins which would be difficult to transport in their fully translated, terminally-folded state. This, therefore, highlights a critical requirement in these cells for local control of protein translation, which is achieved through specific trafficking of mRNAs to each process and local translation therein. Given that a large number of RNA-binding proteins have been implicated in ALS, and RNA-binding proteins are essential for trafficking mRNAs from the nucleus to glial processes for local translation, RNA misprocessing in glial cells is a likely source of cellular dysfunction in ALS. To date, neurons have been the focus of ALS research, but an intrinsic deficit in glia, namely astrocytes and oligodendrocytes, could have an additive effect on declining neuronal function in ALS. This review article aims to highlight the key evidence that supports the contention that RNA trafficking deficits in astrocytes and oligodendrocytes may contribute to in ALS

A systematic review of the epidemiology of hepatitis A in Africa

Abstract Background Hepatitis A, caused by the hepatitis A virus (HAV), is a vaccine preventable disease. In Low and Middle-Income Countries (LMICs), poor hygiene and sanitation conditions are the main risk factors contributing to HAV infection. There have been, however, notable improvements in hygiene and sanitation conditions in many LMICs. As a result, there are studies showing a possible transition of some LMICs from high to intermediate HAV endemicity. The World Health Organization (WHO) recommends that countries should routinely collect, analyse and review local factors (including disease burden) to guide the development of hepatitis A vaccination programs. Up-to-date information on hepatitis A burden is, therefore, critical in aiding the development of country-specific recommendations on hepatitis A vaccination. Methods We conducted a systematic review to present an up-to-date, comprehensive synthesis of hepatitis A epidemiological data in Africa. Results The main results of this review include: 1) the reported HAV seroprevalence data suggests that Africa, as a whole, should not be considered as a high HAV endemic region; 2) the IgM anti-HAV seroprevalence data showed similar risk of acute hepatitis A infection among all age-groups; 3) South Africa could be experiencing a possible transition from high to intermediate HAV endemicity. The results of this review should be interpreted with caution as the reported data represents research work with significant sociocultural, economic and environmental diversity from 13 out of 54 African countries. Conclusions Our findings show that priority should be given to collecting HAV seroprevalence data and re-assessing the current hepatitis A control strategies in Africa to prevent future disease outbreaks

Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts

Acknowledgements This work would not be possible without the resources of the Edinburgh Brain Bank, and the tissue donors and their families. Funding This research was funded in part by the Wellcome Trust (108890/Z/15/Z) to O.M.R., a Pathological Society of Great Britain & Ireland and Jean Shanks Foundation grant (JSPS CLSG 202002) to J.M.G. and J.O., a National Institutes of Health (NIH) grant (5-R01-NS127186-02) to J.M.G., F.M.W., and J.O., a Motor Neuron Disease (MND) Scotland grant to J.M.G. and C.R.S. (2021/MNDS/RP/8440GREG), and a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (215454/Z/19/Z) to C.R.S.Peer reviewedPublisher PD

Distinct neuroinflammatory signatures exist across genetic and sporadic ALS cohorts

Acknowledgments This research was funded in part by the Wellcome Trust (108890/Z/15/Z) to OMR, a Pathological Society and Jean Shanks Foundation grant (JSPS CLSG 202002) to JMG and JOS, an NIH grant (5-R01-NS127186-02) to JMG, FMW, and JOS, a Motor Neuron Disease (MND) Scotland grant to JMG and CRS (2021/MNDS/RP/8440GREG), and a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (215454/Z/19/Z) to CRS. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This work would not be possible without the resources of the Edinburgh Brain Bank. The authors declare no conflicts of interest.Preprin

40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?

AM is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). He also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic (ARRNC), University of Edinburgh, and a seedcorn grant from The Chief Scientist Office and the RS Macdonald Charitable Trust via the Scottish Neurological Research Fund, administered by the University of St Andrews. The Hardingham and Chandran laboratories are supported by the Euan MacDonald Centre for Motor Neurone Disease Research, and the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd., funded by the MRC, Alzheimer’s Society and Alzheimer’s Research UK.Peer reviewedPublisher PD