Synaptic disruption and CREB-regulated transcription are restored by K⁺ channel blockers in ALS.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which is still missing effective therapeutic strategies. Although manipulation of neuronal excitability has been tested in murine and human ALS models, it is still under debate whether neuronal activity might represent a valid target for efficient therapies. In this study, we exploited a combination of transcriptomics, proteomics, optogenetics and pharmacological approaches to investigate the activity-related pathological features of iPSC-derived C9orf72-mutant motoneurons (MN). We found that human ALS^C9orf72 MN are characterized by accumulation of aberrant aggresomes, reduced expression of synaptic genes, loss of synaptic contacts and a dynamic "malactivation" of the transcription factor CREB. A similar p

SUBMITTER: Catanese A 

PROVIDER: S-EPMC8261490 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature