Non-neuronal cells in amyotrophic lateral sclerosis — from pathogenesis to biomarkers

Abstract

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The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

“…While TDP-43 inclusions are present in most ALS cases, including TDP-43 , FUS , and C9ORF72 mutation carriers, these aggregates do not appear in SOD1 mutation carriers. Moreover, selective expression of SOD1 and TDP-43 specific mutations in mouse MNs is sufficient to induce neurodegeneration [ 42 , 43 , 44 , 45 ], but not in all cases [ 46 ], suggesting that other molecular mechanisms could be implicated in the pathogenesis. Surprisingly, overexpression of SOD1-G93A mutation in mouse microglia showed high expression of M2 phenotype at a presymptomatic stage and reduced M2 and increased M1 markers at the late stage of the disease [ 47 ].…”

Convergent transcriptomic targets of propranolol and primidone identify potential biomarkers for essential tremor

“…Oligodendrocytes, whose dysfunction contributes to numerous other neurological diseases, also showed an enrichment of propranolol and primidone-targeted genes. Both astrocytes and oligodendrocytes might be targeted by ET drugs to reduce tremor since non-neuronal cell types are known to be involved in neurodegeneration in numerous diseases 43 . The lack of single-cell data on ET tissues is a limitation in the study of this disease but our results highlight a possible role for non-neuronal cells in the cerebellum in ET.…”

Taking Cellular Heterogeneity Into Consideration When Modeling Astrocyte Involvement in Amyotrophic Lateral Sclerosis Using Human Induced Pluripotent Stem Cells

“…A number of previous studies suggest that motor neuron degeneration in ALS is not only caused by cell-autonomous cell death mechanisms but can also result from non-cell autonomous processes involving non-neuronal cells such as astrocytes and microglia (previously reviewed by Serio and Patani, 2018;Izrael et al, 2020;Vahsen et al, 2021;Van Harten et al, 2021). Evidence suggesting abnormal activation of astrocytes in ALS initially came from the analysis of post-mortem tissues, cerebrospinal fluids and blood samples from ALS patients (Schiffer et al, 1996;Poloni et al, 2000;Anneser et al, 2004;Baron et al, 2005), as well as the detection of marked neuroinflammation in the spinal cord and cranial motor nuclei in ALS transgenic mouse models (Schiffer et al, 1996;Ferraiuolo et al, 2007;Evans et al, 2014).…”

“…Consistent with original post mortem/in vivo observations, several studies based on in vitro cultures of neural cells provided evidence that astrocytes harboring ALS-associated mutated proteins, such as mutated SOD1, are toxic to primary, as well as pluripotent stem cell-derived, motor neurons, but not to other neuronal populations (Di Giorgio et al, 2007Nagai et al, 2007;Marchetto et al, 2008). These findings led to the suggestion that astrogliosis induced in response to initial insults to motor neurons gradually progresses from an initially neuroprotective role to neuroinflammatory effects that exacerbate neuronal degeneration (previously reviewed by Serio and Patani, 2018;Izrael et al, 2020;Vahsen et al, 2021). It is generally hypothesized that astrocytes exert deleterious effects on motor neuron in ALS as a consequence of either loss of supportive functions or gain of toxic functions (or a combination of both).…”