Non‐neuronal Cells in ALS: Role of Glial, Immune cells and Blood‐CNS Barriers

Abstract

Neurological dysfunction and motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is strongly associated with neuroinflammation reflected by activated microglia and astrocytes in the CNS. In ALS endogenous triggers in the CNS such as aggregated protein and misfolded proteins activate a pathogenic response by innate immune cells. However, there is also strong evidence for a neuroprotective immune response in ALS. Emerging evidence also reveals changes in the peripheral adaptive immune responses as well as alterations in the blood brain barrier that may aid traffic of lymphocytes and antibodies into the CNS. Understanding the triggers of neuroinflammation is key to controlling neuronal loss. Here, we review the current knowledge regarding the roles of non-neuronal cells as well as the innate and adaptive immune responses in ALS. Existing ALS animal models, in particular genetic rodent models, are very useful to study the underlying pathogenic mechanisms of motor neuron degeneration. We also discuss the approaches used to target the pathogenic immune responses and boost the neuroprotective immune pathways as novel immunotherapies for ALS.

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…As a result, the tissue pH decreases, which alters protein folding and induces aggregate formation, as observed with Amyloid-β [89]. In ALS, this dynamic adaptation of the glial phenotype to the graded metabolic and structural modifications results in an overproduction of neurotoxic molecules and chronic neuroinflammation ( Figure 2) which drives, at least in part, the disease progression [77,[90][91][92] .…”

“…A growing body of evidence supports this hypothesis. For example, circulating myeloid cells of ALS patients have a proinflammatory phenotype [90,176], while regulatory T lymphocytes are decreased, enhancing neuroinflammation and disease progression [177]. Also, the up-regulation of inflammatory genes in arrays on samples from ALS patients suggests the involvement of immune actions in the ALS pathogenesis [178][179][180].…”

Evidence for an early innate immune response in the motor cortex of ALS

“…This leads to failure of the motor neuron circuitry and the neuromuscular system with loss of voluntary movement [1]. Even though ALS is manifested by progressive degeneration of motor neurons, the role and the impact of non-neuronal cells in the environment have been suggested as being important for both for the initiation and progression of the disease [2] and they are now considered as an integral part of disease pathology in ALS [3]. …”

Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular development and homeostasis

“…We have therefore shown that the vascular system is unaffected in Gars C201R/+ mice from embryonic development to adulthood. Extra-neuronal tissue pathology and disease mechanisms have been reported in mouse models of a number of peripheral nerve conditions including spinal muscular atrophy (Sleigh et al, 2011), Kennedy's disease (Cortes et al, 2014;Lieberman et al, 2014), and amyotrophic lateral sclerosis (Puentes et al, 2016), appearing to mirror the human conditions, at least in some of their most debilitating incarnations (Somers et al, 2016). Nevertheless, we have convincingly .…”