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Obatoclax rescues FUS-ALS phenotypes in iPSC-derived neurons by inducing autophagy

ABSTRACT: Disruption of protein homeostasis plays an essential role in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). One strategy for restoring protein homeostasis and protecting neurons is to de-repress autophagy by disrupting the inhibitory BECN1/BCL2 complex, which has been shown to improve healthspan and lifespan in mice. We screened small molecule BH3 mimetics using an induced pluripotent stem cell (iPSC)-based model of ALS with a FUS mutation and identified obatoclax rescued neurons at by reducing cytoplasmic FUS levels, restoring protein homeostasis, and reducing degeneration.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Marc Gentzel

LAB HEAD: Prof. Dr. Jared Sterneckert

PROVIDER: PXD042427 | Pride | 2023-10-16

REPOSITORIES: Pride

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			Action	DRS
	20230501_D3000_ACCLAIM_DIA_CCBJS04_01_RTSTD_R120R015_NCE27_50ms_090min_01.raw	Raw
	20230501_D3000_ACCLAIM_DIA_CCBJS04_02_RTSTD_R120R015_NCE27_50ms_090min_01.raw	Raw
	20230501_D3000_ACCLAIM_DIA_CCBJS04_03_RTSTD_R120R015_NCE27_50ms_090min_01.raw	Raw
	20230501_D3000_ACCLAIM_DIA_CCBJS04_04_RTSTD_R120R015_NCE27_50ms_090min_01.raw	Raw
	20230501_D3000_ACCLAIM_DIA_CCBJS04_05_RTSTD_R120R015_NCE27_50ms_090min_01.raw	Raw

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ALS-causative mutations in FUS/TLS confer gain- and loss-of-function by altered association with SMN and U1-snRNP

Project description:The RNA-binding protein FUS/TLS, mutation in which is causative of the fatal motor neuron disease ALS, is demonstrated to directly bind to the U1-snRNP and SMN complexes. ALS-causative mutations in FUS/TLS are shown to abnormally enhance their interaction with SMN and reduce interaction with U1-snRNP. Correspondingly, global RNA analysis reveals a mutant-dependent loss of splicing activity, with ALS-linked mutants failing to reverse changes caused by loss of wild-type FUS/TLS. Furthermore, a common FUS/TLS mutant-associated RNA splicing signature is identified in ALS patient fibroblasts. Taken together, our studies establish potentially converging disease mechanisms in ALS and spinal muscular atrophy, with ALS-causative mutants acquiring properties representing both gain (dysregulation of SMN) and loss (reduced RNA processing mediated by U1-snRNP) of function. RNA-mediated oligonucleotide Annealing, Selection, and Ligation with Next-Generation sequencing (RASL-seq) method was used for analyzing alternative splicing changes. Oligonucleotide probes are designed to anneal to the exon-exon junctions. The probe library was assembled to assess 5530 unique alternative splicing events, most of which were exon inclusion or skipping, with a minority for alternative 5’- or 3’- splice sites. The splicing changes were compared among groups of reducing FUS/TLS or SMN levels, or expressing various FUS mutations to determine the loss versus gain of FUS/TLS function on splicing regulation.

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