ALS is a devastating neurological disease causing progressive and relentless paralysis over months to years until death from respiratory failure. ALS kills 1 in every 300 people and is the commonest reason to seek assisted suicide. The aim of the STRENGTH consortium is to identify factors that affect susceptibility to ALS or modify the pattern of ALS onset or survival duration as targets for the development of new therapies. Until now, the usual approach has been to consider ALS as a homogeneous disease and identify genetic or environmental risk factors. STRENGTH uses a novel approach, first using clinical, laboratory and sophisticated clustering methods to identify homogeneous patient subgroups to increase power, and second using multiple layers of data from environmental questionnaires and genetics from the same individuals enrolled in pan-European population registers covering a population of about 120 million people, to identify for the first time how risk and protective factors work in concert to cause and modify ALS. In addition, STRENGTH partners include epigeneticists, able to develop this field in ALS and to further reveal the interface between genetic and environmental interaction. STRENGTH capitalises on existing infrastructure from the EU funded EuroMOTOR project which enables collection of large data sets, and the JPND funded SOPHIA project which ensures the data collection follows standard operating procedures throughout Europe, and will enable the discovery of new pharmaceutical targets for ALS.

Glycosphingolipids (GSLs) synthesized in the Golgi and endoplasmic reticulum are incredibly diverse but are essential for membranes, lipid rafts, the glycocalyx, lysosomal function; small changes can have major effects, but their immense diversity the sugar and lipid moieties poses difficulties in analysis. Using metabolomics, the consortium found that the ceramide/glucosylceramide ration is critically modified in ALS models, and patients. Glucosylceramidase (subtype GBA2, non-lysosomal) is a critical determinant of amyotrophic lateral sclerosis (ALS) and denervation (Dodge, Henriques et al refs), being upregulated 8-10 fold in early stages of denervation in SOD1G86R mice. In contrast, mutations in lysosomal glucosylceramidase (GBA1) is the most frequent mutation associated with Parkinsons disease and has an inverse relationship with a-synuclein. Lysosomal disorders, with a massive increase in lysosomal glucosylceramide, include Neumann-Pick disease, Gaucher Disease are associated with frequent neurological impact. Drugs such as ambroxol which is an inhibitor of GBA2 while being a chaperone for GBA1 are in development for ALS and Parkinsons disease. However, GSL diversity is recognized by envelope viruses such as SARS-CoV-2, which target neurotrophic GSLs specifically at nearly stages of viral entry, and exit, using Golgi/ER membranes to form their envelopes ,which consist of cholesterol and GSLs. Remarkably, the same glucosylceramidase (and glucosylceramide synthase, GCS) enzymes critical to neurodegeration are critical for envelope virus replication. The viruses massively change lipid metabolism, oxygen use, (Perera), and can deplete neurotrophic GSLs such as GM1, a 5-sugar GSL, which is a target for cholera toxin, influenza virus, and also SARS-CoV-2. Microglia detect the changed metabolism and clear virus-infected neurons, detecting them via specific mitochondria /microglial/neuronal structures with ATP P2Y12 receptors (detecting ADP) and P2X7 receptors linked to inflammasomes, producing IL1b which by promoting glycolysis, extends brain lesions. Thus metabolic effects of viral infections in the brain appear to be monitored by microglia, via P2Y12 receptors, and if necessary clearing neurons by recruiting monocytes (brain fog? Cserep et al 2020, 2021, Fekete et al 2018; A Denes). The consortium will work on nomenclature, methodology, data (including complex metabolomics) to produce position papers and proposed new directions for neurodegenerative disease, COVID infections and long-COVID. IUPHAR will create an official subcommittee on GSLs to quality control and reinforce recommendations.