The Use of Stem Cells to Model Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: From Basic Research to Regenerative Medicine

Table 2

Observations from stem cell derived models of known ALS/FTD genes.

Aberrant gene	Differentiated cell type	Main observations	Associated disease	Reference
C9ORF72	hiPSC derived neurons	RNA foci, RAN translation products, and increased susceptibility to cellular stress caused by autophagy inhibition	ALS/FTD	[22]
	hiPSC derived neurons	Specific susceptibility to glutamate excitotoxicity and mitigation of C9ORF72 phenotype with antisense oligonucleotides therapeutics	ALS/FTD	[23]
	hiPSC derived MNs	Transcriptional changes and presence of RNA foci	ALS/FTD	[24]
C9ORF72/TARDBP	hiPSC derived MNs	Neuronal hyperexcitability followed by progressive loss of action potential output and synaptic activity	ALS/FTD	[52]
PGRN	hiPSC derived neurons	Increased sensitivity to kinase inhibition, reduced S6K2 levels, and neurite degeneration in absence of glia	FTD	[19]
	hiPSC derived neurons	Identification and validation of small molecules with therapeutic potential	FTD	[53]
TARDBP	hiPSC derived MNs	Mislocalization of TDP-43, decreased MN survival rate, and increased vulnerability to inhibition of the PI3K pathway	ALS/FTD	[17]
	hiPSC derived MNs	Identification of the histone acetyltransferase inhibitor anacardic acid as able to reverse disease phenotype	ALS/FTD	[35]
	hiPSC derived MNs	TDP-43 aggregation and feasibility of hiPSCs derived MNs for drug screening	ALS/FTD	[21]
TARDBP/SOD1	mESC derived MNs/hiPSCs derived MNs	Kenpaullone, a GSK3-inhibitor, increased survival of MNs more so than two potential therapeutic compounds that failed in clinical trials (olesoxime and dexpramipexole)	ALS	[32]
SOD1	hESC derived MNs/glia cells	MNs were shown to be selectively sensitive to toxic effects of cocultured SOD1 glial cells	ALS	[30]
	hESC derived MNs/astrocytes	Selective MN toxicity correlates with increased inflammatory response in SOD1 astrocytes	ALS	[31]
	hiPSC derived MNs	Identification of misregulated neurofilament	ALS	[27]
SOD1/C9ORF72	hiPSC derived MNs	Potential correlation between SOD1 and C9ORF72 pathogenesis, including elevated oxidative stress response	ALS	[20]

hiPSC = human induced pluripotent stem cell; mESC = mouse embryonic stem cell; hESC = human embryonic stem cell; MN = motor neuron.