Most cases of neurodegenerative diseases are sporadic, hindering the use of genetic mouse models to analyze disease mechanisms. Focusing on the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS), we therefore devised a fully humanized coculture model composed of human adult primary sporadic ALS (sALS) astrocytes and human embryonic stem-cell-derived MNs. The model reproduces the cardinal features of human ALS: sALS astrocytes, but not those from control patients, trigger selective death of MNs. The mechanisms underlying this non-cell-autonomous toxicity were investigated in both astrocytes and MNs. Although causal in familial ALS (fALS), SOD1 does not contribute to the toxicity of sALS astrocytes. Death of MNs triggered by either sALS or fALS astrocytes occurs through necroptosis, a form of programmed necrosis involving receptor-interacting protein 1 and the mixed lineage kinase domain-like protein. The necroptotic pathway therefore constitutes a potential therapeutic target for this incurable disease.

The expansion of a hexanucleotide (GGGGCC) repeat inC9ORF72is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both the function of C9ORF72 and the mechanism by which the repeat expansion drives neuropathology are unknown. To examine whether C9ORF72 haploinsufficiency induces neurological disease, we created a C9orf72-deficient mouse line. Null mice developed a robust immune phenotype characterized by myeloid expansion, T cell activation and increased plasma cells. Mice also presented with elevated autoantibodies and evidence of immune-mediated glomerulonephropathy. Collectively, our data suggest that C9orf72 regulates immune homeostasis and an autoimmune response reminiscent of systemic lupus erythematosus (SLE) occurs in its absence. We further imply that haploinsufficiency is unlikely to be the causative factor in C9ALS/FTD pathology.

Neurodegenerative phenotypes reflect complex, time-dependent molecular processes whose elucidation may reveal neuronal class-specific therapeutic targets. The current focus in neurodegeneration has been on individual genes and pathways. In contrast, we assembled a genome-wide regulatory model (henceforth, "interactome"), whose unbiased interrogation revealed 23 candidate causal master regulators of neurodegeneration in an in vitro model of amyotrophic lateral sclerosis (ALS), characterized by a loss of spinal motor neurons (MNs). Of these, eight were confirmed as specific MN death drivers in our model of familial ALS, including NF-κB, which has long been considered a pro-survival factor. Through an extensive array of molecular, pharmacological, and biochemical approaches, we have confirmed that neuronal NF-κB drives the degeneration of MNs in both familial and sporadic models of ALS, thus providing proof of principle that regulatory network analysis is a valuable tool for studying cell-specific mechanisms of neurodegeneration.

Optimal brain health is essential to smoothing major global skill-intensive economic transitions, such as the bioeconomy, green, care economy and digital transitions. Good brain health is vital to socio-economic sustainability, productivity and well-being. The care transition focuses on recognizing and investing in care services and care work as essential for economic growth and social well-being. The green transition involves shifting towards environmentally sustainable and fairer societies to combat climate change and environmental degradation. The digital transition aims to unlock digital growth potential and deploy innovative solutions for businesses and citizens, and to improve the accessibility and efficiency of services. The bioeconomy transition refers to the shift towards an economy based on products, services and processes derived from biological resources, such as plants and microorganisms. Brain capital, which encompasses brain health and brain skills, is a critical economic asset for the success of economies of the future. The brain economy transition from a brain-negative (brain-unhealthy) economy, which depletes brain capital, to a brain-positive (brain-healthy) economy, which arrests and reverses the loss of brain capital, will be foundational to these major transitions. Increased brain capital is vital to educational attainment, upskilling and reskilling. In this paper, we provide a detailed roadmap for the brain economy transition.