Why should we care about astrocytes in a motor neuron disease?

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults, causing progressive degeneration of motor neurons, which results in muscle atrophy, respiratory failure and ultimately death of the patients. The pathogenesis of ALS is complex, and extensive efforts have focused on unravelling the underlying molecular mechanisms with a large emphasis on the dying motor neurons. However, a recent shift in focus towards the supporting glial population has revealed a large contribution and influence in ALS, which stresses the need to explore this area in more detail. Especially studies into astrocytes, the residential homeostatic supporter cells of neurons, have revealed a remarkable astrocytic dysfunction in ALS, and therefore could present a target for new and promising therapeutic entry points. In this review, we provide an overview of general astrocyte function and summarize the current literature on the role of astrocytes in ALS by categorizing the potentially underlying molecular mechanisms. We discuss the current efforts in astrocyte-targeted therapy, and highlight the potential and shortcomings of available models.

Mature iPSC-derived astrocytes of an ALS/FTD patient carrying the TDP43A90V mutation display a mild reactive state and release polyP toxic to motoneurons

“…Our results with mutant TARDBP astrocytes are in agreement with a large number of previous studies showing that, independent of the genotype, fALS and fALS/FTD ( SOD1, TARDBP, C9ORF72 and VCP ) as well as sALS astrocytes, can reduce the number of healthy wild-type MNs in co-cultures or after addition of their ACM to MN cultures ( van Harten et al, 2021 ; Stoklund Dittlau and Van Den Bosch, 2023 ; and references included in the introduction). However, there are also reports using human iPSC-derived astrocytes that do not fully support this conclusion.…”

“…Evidence from animal models indicate that astrocytes contribute to motoneuron (MN) degeneration and are important players in the onset and progression of ALS ( Clement et al, 2003 ; Lepore et al, 2008 ; Yamanaka et al, 2008 ; Ilieva et al, 2009 ; Papadeas et al, 2011 ; Wang et al, 2011 ; van Zundert et al, 2012 ; Qian et al, 2017 ; Tong et al, 2013 ; Ramírez-Jarquín et al, 2017 ). Astrocytic non-cell autonomous processes have also been demonstrated in multiple mouse and human cell-based assays ( van Harten et al, 2021 ; Stoklund Dittlau and Van Den Bosch, 2023 ). Thus, primary ALS and ALS/FTD astrocytes derived from transgenic mouse models harboring pathogenic gene mutations in SOD1, TARDBP and C9ORF72 reduce the number of healthy wild-type MNs in co-cultures or after application of astrocyte conditioned media (ACM) ( Vargas et al, 2006 ; Di Giorgio et al, 2007 ; Nagai et al, 2007 ; Fritz et al, 2013 ; Re et al, 2014 ; Rojas et al, 2014 ; Ikiz et al, 2015 ; Rojas et al, 2015 ; Jury et al, 2020 ; Mishra et al, 2020 ; Arredondo et al, 2022 ).…”

“…Recent analyses of iPSC cell-based models further suggest that toxic effects of human astrocytes on MN survival and neurite outgrowth may also be the result of an enhanced secretion of inflammatory cytokines from reactive FUS-ALS astrocytes ( Stoklund Dittlau et al, 2022 ) as well as increased release of ATP released through the opening of Cx43 hemichannels that are upregulated in fALS SOD1 and sALS astrocytes ( Almad et al, 2022 ). Conversely, loss of neuron-supportive mechanisms has also been proposed to contribute to MN death and impaired neurite network maintenance ( Stoklund Dittlau and Van Den Bosch, 2023 ). Specifically, it was found that ACM and/or extracellular vesicles released from diverse human ALS astrocytes subtypes was toxic to MNs due to decreased levels of miR-494-3p in C9ORF72-ALS ( Varcianna et al, 2019 ), reduced levels of miR-146a in SOD1-ALS and sALS ( Gomes et al, 2022 ), and lower concentrations of anti-oxidant proteins in C9ORF72-ALS ( Birger et al, 2019 ).…”

Genetic Downregulation of the Metabotropic Glutamate Receptor Type 5 Dampens the Reactive and Neurotoxic Phenotype of Adult ALS Astrocytes

“…ALS is associated with altered cellular metabolism that involves MNs and other CNS cells, including astrocytes [92][93][94]. We investigated here whether the positive shift of the altered astrocyte phenotype obtained by the constitutive mGluR5 genetic downregulation was also paralleled by the amelioration of the energetic profile of these cells.…”

AMPKα1 Deficiency in Astrocytes from a Rat Model of ALS Is Associated with an Altered Metabolic Resilience

“…The neurocentric view of ALS has been challenged in recent decades by a strong body of research pointing out at glial cells as main contributors to the progression of the disease [ 19 , 20 , 21 ]. In particular, astrocytes provide essential trophic, metabolic, and protective support to neurons, and a dysregulation of astrocytic functions has been shown to contribute to several pathogenic mechanisms occurring in ALS [ 22 , 23 ]. For instance, a reduced expression/activity of glial glutamate transporters, as well as an elevated extracellular concentration of glutamate, have been reported in the CNS of both patients and animal models of ALS, contributing to excitotoxic damages to neurons [ 24 , 25 , 26 , 27 , 28 , 29 ].…”