The role of glial cells in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) has traditionally been considered a neuron-centric disease. This view is now outdated, with increasing recognition of cell autonomous and non-cell autonomous contributions of central and peripheral nervous system glia to ALS pathomechanisms. With glial research rapidly accelerating, we comprehensively interrogate the roles of astrocytes, microglia, oligodendrocytes, ependymal cells, Schwann cells and satellite glia in nervous system physiology and ALS-associated pathology. Moreover, we highlight the inter-glial, glial-neuronal and inter-system polylogue which constitutes the healthy nervous system and destabilises in disease. We also propose classification based on function for complex glial reactive phenotypes and discuss the pre-requisite for integrative modelling to advance translation. Given the paucity of life-enhancing therapies currently available for ALS patients, we discuss the promising potential of harnessing glia in driving ALS therapeutic discovery.

A Non-Toxic Concentration of Telomerase Inhibitor BIBR1532 Fails to Reduce TERT Expression in a Feeder-Free Induced Pluripotent Stem Cell Model of Human Motor Neurogenesis.

Several studies have shown that human induced pluripotent stem cell (iPSC)-derivatives are essentially fetal in terms of their maturational status. Inducing ageing in iPSC-motor neuron (MN) models of amyotrophic lateral sclerosis (ALS) has the potential to capture pathology with higher fidelity and consequently improve translational success. We show here that the telomerase inhibitor BIBR1532, hypothesised to recapitulate the telomere attrition hallmark of ageing in iPSC-MNs, was in fact cytotoxic to feeder-free iPSCs when used at doses previously shown to be effective in iPSCs grown on a layer of mouse embryonic fibroblasts. Toxicity in feeder-free cultures was not rescued by co-treatment with Rho Kinase (ROCK) inhibitor (Y-27632). Moreover, the highest concentration of BIBR1532 compatible with continued iPSC culture proved insufficient to induce detectable telomerase inhibition. Our data suggest that direct toxicity by BIBR1532 is the most likely cause of iPSC death observed, and that culture methods may influence enhanced toxicity. Therefore, recapitulation of ageing hallmarks in iPSC-MNs, which might reveal novel and relevant human disease targets in ALS, is not achievable in feeder-free culture through the use of this small molecule telomerase inhibitor.

Region-specific vulnerability in neurodegeneration: lessons from normal ageing.

A number of age-associated neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), possess a shared characteristic of region-specific neurodegeneration. However, the mechanisms which determine why particular regions within the nervous system are selectively vulnerable to neurodegeneration, whilst others remain relatively unaffected throughout disease progression, remain elusive. Here, we review how regional susceptibility to the ubiquitous physiological phenomenon of normal ageing might underlie the vulnerability of these same regions to neurodegeneration, highlighting three regions archetypally associated with AD, PD and ALS (the hippocampus, substantia nigra pars compacta and ventral spinal cord, respectively), as especially prone to age-related alterations. Placing particular emphasis on these three regions, we comprehensively explore differential regional susceptibility to nervous system tissue, cellular and molecular level ageing to provide an integrated perspective on why age-related neurodegenerative diseases exhibit region-selective vulnerability. Combining these principles with increasingly recognised differences between chronological and biological ageing (termed differential or 'delta' ageing) might ultimately guide therapeutic approaches for these devastating neurodegenerative diseases, for which a paucity of disease modifying and/or life promoting treatments currently exist.

Decoding the relationship between ageing and amyotrophic lateral sclerosis: a cellular perspective.

With an ageing population comes an inevitable increase in the prevalence of age-associated neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), a relentlessly progressive and universally fatal disease characterized by the degeneration of upper and lower motor neurons within the brain and spinal cord. Indeed, the physiological process of ageing causes a variety of molecular and cellular phenotypes. With dysfunction at the neuromuscular junction implicated as a key pathological mechanism in ALS, and each lower motor unit cell type vulnerable to its own set of age-related phenotypes, the effects of ageing might in fact prove a prerequisite to ALS, rendering the cells susceptible to disease-specific mechanisms. Moreover, we discuss evidence for overlap between age and ALS-associated hallmarks, potentially implicating cell type-specific ageing as a key contributor to this multifactorial and complex disease. With a dearth of disease-modifying therapy currently available for ALS patients and a substantial failure in bench to bedside translation of other potential therapies, the unification of research in ageing and ALS requires high fidelity models to better recapitulate age-related human disease and will ultimately yield more reliable candidate therapeutics for patients, with the aim of enhancing healthspan and life expectancy.