Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by the selective loss of the upper and lower motor neurons. Only 10% of all cases are caused by a mutation in one of the two dozen different identified genes, while the remaining 90% are likely caused by a combination of as yet unidentified genetic and environmental factors. Mutations in C9orf72, SOD1, or TDP-43 are the most common causes of familial ALS, together responsible for at least 60% of these cases. Remarkably, despite the large degree of heterogeneity, all cases of ALS have protein aggregates in the brain and spinal cord that are immunopositive for SOD1, TDP-43, OPTN, and/or p62. These inclusions are normally prevented and cleared by heat shock proteins (Hsps), suggesting that ALS motor neurons have an impaired ability to induce the heat shock response (HSR). Accordingly, there is evidence of decreased induction of Hsps in ALS mouse models and in human post-mortem samples compared to unaffected controls. However, the role of Hsps in protein accumulation in human motor neurons has not been fully elucidated. Here, we generated motor neuron cultures from human induced pluripotent stem cell (iPSC) lines carrying mutations in SOD1, TDP-43, or C9orf72. In this study, we provide evidence that despite a lack of overt motor neuron loss, there is an accumulation of insoluble, aggregation-prone proteins in iPSC-derived motor neuron cultures but that content and levels vary with genetic background. Additionally, although iPSC-derived motor neurons are generally capable of inducing the HSR when exposed to a heat stress, protein aggregation itself is not sufficient to induce the HSR or stress granule formation. We therefore conclude that ALS iPSC-derived motor neurons recapitulate key early pathological features of the disease and fail to endogenously upregulate the HSR in response to increased protein burden.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal, adult onset neurodegenerative disorder caused by the loss of the upper and lower motor neurons
While motor neuron loss is a key feature of familial ALS (fALS) and sALS, previous in vitro studies have shown that induced pluripotent stem cell (iPSC)-derived motor neurons do not exhibit reduced viability when grown in the absence of astrocytes (Egawa et al, 2012; Almeida et al, 2013; Chen et al, 2014; Devlin et al, 2015)
Consistent with previous reports, there was no difference in the number of motor neurons in SOD1, C9orf72, or TDP-43 cultures compared to controls at 4 weeks in culture (Figure 1)
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal, adult onset neurodegenerative disorder caused by the loss of the upper and lower motor neurons. Protein Aggregation in ALS heterogeneity of sALS, have made identifying convergent mechanisms of this disease challenging. Despite this difficulty, a few similarities have been identified between all cases of ALS, including the presence of protein aggregates in the brain or spinal cord (Mizuno et al, 2006). A few similarities have been identified between all cases of ALS, including the presence of protein aggregates in the brain or spinal cord (Mizuno et al, 2006) These inclusions typically contain a core set of proteins, including SOD1, TDP-43, and optineurin (OPTN), to name a few. Given the known toxic effects of protein aggregates (Boya et al, 2003; De Kimpe et al, 2013; Yu et al, 2014), attempting to clear these aggregates represents a desirable therapeutic target that could be broadly applicable
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