Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which upper and lower motor neuron loss is the primary phenotype, leading to muscle weakness and wasting, respiratory failure, and death. Although a portion of ALS cases are linked to one of over 50 unique genes, the vast majority of cases are sporadic in nature. However, the mechanisms underlying the motor neuron loss in either familial or sporadic ALS are not entirely clear. Here, we used induced pluripotent stem cells derived from a set of identical twin brothers discordant for ALS to assess the role of astrocytes and microglia on the expression and accumulation of neurofilament proteins in motor neurons. We found that motor neurons derived from the affected twin which exhibited increased transcript levels of all three neurofilament isoforms and increased expression of phosphorylated neurofilament puncta. We further found that treatment of the motor neurons with astrocyte-conditioned medium and microglial-conditioned medium significantly impacted neurofilament deposition. Together, these data suggest that glial-secreted factors can alter neurofilament pathology in ALS iPSC-derived motor neurons.
Highlights
Published: 27 January 2022Amyotrophic lateral sclerosis (ALS) is a severe and always fatal neurodegenerative disease in which upper and lower motor neurons are lost leading to muscle weakness, paralysis, and death typically within 2–5 years of diagnosis
Here we used RNA sequencing on the motor neurons to get a better global picture of transcriptional signatures between the affected and unaffected cells to identify molecular pathways that may be involved in motor neuron malfunction and loss
We found 40,418 transcripts to be differentially expressed between the cells, with 3086 significantly upregulated and 2321 significantly downregulated in the affected motor neurons compared to the healthy control (Figure 1A,B)
Summary
Amyotrophic lateral sclerosis (ALS) is a severe and always fatal neurodegenerative disease in which upper and lower motor neurons are lost leading to muscle weakness, paralysis, and death typically within 2–5 years of diagnosis. ALS has been causally linked to several different genetic mutations, but the vast majority of cases are still sporadic in nature with no known genetic cause [1]. Various mechanisms have been postulated as leading to the motor neuron loss [1], there is still a lack of clear understanding of motor neuron degeneration in ALS. Despite an unknown cause of motor neuron loss, intracellular inclusions of aggregated proteins are clear pathological hallmarks that span both sporadic and familial ALS patient samples [2]. The alteration of neurofilament level is of particular interest in ALS because neurofilament is found in high abundance in the cerebral
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