The multifaceted role of glial cells in amyotrophic lateral sclerosis

Abstract

Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia-neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS.

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…Analysis of various types of these models revealed the primary role of astroglia in pathology. Astroglial degeneration and atrophy associated with the loss of function precede neuronal death and occur before the emergence of clinical symptoms (Valori, Brambilla, Martorana, & Rossi, 2014; Verkhratsky, Parpura, Pekna, Pekny & Sofroniew, 2014). When SOD1 was specifically expressed in astrocytes, it made them highly vulnerable to extracellular glutamate and resulted in secretion of several neurotoxic factors.…”

Astroglial calcium signalling in Alzheimer's disease

“…In astrocytes exposed to antibodies isolated from ALS patients, a massive alteration in vesicle dynamics and Ca 2+ homeostasis has been reported [79,80]. In the animal model of ALS expressing human mutant superoxide dismutase 1 (Tg(SOD1*G93A)1Gur mice), the emergence of atrophic astrocytes is the earliest pathological signature [81][82][83]; these atrophic astrocytes down-regulate glutamate uptake and become vulnerable to glutamate by themselves. Deficient astrocytes, therefore, provide a background for developing glutamate excitotoxicity that leads to neuronal death [72].…”

Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery

“…C. elegans relies on an evolutionary conserved, innate immune response (Engelmann and Pujol, 2010) that coordinates its activity with the insulin/IGF-1 pathway (Singh and Aballay, 2009) suggesting these may be pathways worth investigating. Also, in the past year, a convergence of data has suggested a role for glial cells in ALS neurodegeneration (Parisi et al, 2013;Valori et al, 2013;Chiu et al, 2014). The worm has 56 glial cells and some are found at the neuromuscular junction (Oikonomou and Shaham, 2011).…”