Project description:Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain and spinal cord. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. We report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased, leading to accumulation of GGGGCC repeat–containing RNA foci selectively in C9-ALS iPSC-derived motor neurons. Repeat-containing RNA foci colocalized with hnRNPA1 and Pur-?, suggesting that they may be able to alter RNA metabolism. C9-ALS motor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motor neurons. These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS. Transcriptome profiling from iPSC derived motor neurons compared to controls

2013-11-07 | E-GEOD-52202 | biostudies-arrayexpress

Quantitative comparison between cellular mRNAs and exosomal mRNAs in human iPSC-derived motor neurons

Project description:The order in the abundance of exosomal mRNAs was not the same with that of the source cellular mRNAs in human iPSC-derived motor neurons.

2019-07-30 | GSE135047 | GEO

Co-culture of iPSC-derived microglia and spinal motor neurons as a novel model for amyotrophic lateral sclerosis

Project description:Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder primarily characterized by motor neuron degeneration with additional involvement of non-neuronal cells, in particular, microglia. In our previous work, we have established protocols for the differentiation of iPSC-derived spinal motor neurons and microglia. Here, we combine both cell lineages and establish a novel co-culture of iPSC-derived motor neurons and microglia, which is compatible with motor neuron identity and function. Co-cultured microglia express key microglial markers and transcriptomically resemble primary human microglia, have highly dynamic ramifications, are phagocytic, release various cytokines and respond to stimulation. Further, they express key amyotrophic lateral sclerosis-associated genes and release disease-relevant biomarkers. This novel and authentic human model system facilitates the study of physiological motor neuron-microglia crosstalk and permits the investigation of non-cell-autonomous phenotypes in amyotrophic lateral sclerosis.

2022-07-24 | GSE200037 | GEO

Microglia influence neurofilament deposition in ALS iPSC-derived motor neurons

Project description:Microglia influence neurofilament deposition in ALS iPSC-derived motor neurons

| PRJNA793030 | ENA