Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis

Krach F, Wheeler EC, Regensburger M, Börstler T, Wend H, Vu AQ, Wang R, Reischl S, Boldt K, Batra R, Aigner S, Ravits J, Winkler J, Yeo GW, Winner B (2022)

Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2022

Journal

Acta Neuropathologica Springer

URI: https://link.springer.com/article/10.1007/s00401-022-02450-3#Ack1

DOI: 10.1007/s00401-022-02450-3

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43.

Authors with CRIS profile

Martin Regensburger Professur für Stammzell-Modelle seltener neuraler Erkrankungen Tom Börstler Professur für Stammzell-Modelle seltener neuraler Erkrankungen Jürgen Winkler Professur für Molekulare Neurologie Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

Bavarian Research Association Interaction of Human Brain Cells (ForInter) March 1, 2019 - Dec. 31, 2023 E030: Th17 and beyond: immune-mediated neurotoxicity determines onset and progression in Parkinson’s disease April 1, 2020 - March 31, 2023 E030: Th17 and beyond: immune-mediated neurotoxicity determines onset and progression in Parkinson’s disease April 1, 2020 - March 31, 2023 N2: Sensorbasiertes Monitoring der Gangstörung bei HSP-Patienten mit Umsetzung im AlltagN7: Identifikation der Veränderungen im GSK3-Signalweg bei autosomal-rezessiven Typen der kompliziertenHSP anhand von neuralen Modellen aus induziert-pluripotenten Stammzellen (TreatHSP) N2: Sensorbasiertes Monitoring der Gangstörung bei HSP-Patienten mit Umsetzung im AlltagN7: Identifikation der Veränderungen im GSK3-Signalweg bei autosomal-rezessiven Typen der kompliziertenHSP anhand von neuralen Modellen aus induziert-pluripotenten Stammzellen May 1, 2019 - Jan. 31, 2023

Involved external institutions

Eberhard Karls Universität Tübingen DE Germany (DE) University of California, San Diego US United States (USA) (US)

How to cite

APA:

Krach, F., Wheeler, E.C., Regensburger, M., Börstler, T., Wend, H., Vu, A.Q.,... Winner, B. (2022). Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis. Acta Neuropathologica. https://doi.org/10.1007/s00401-022-02450-3

MLA:

Krach, Florian, et al. "Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis." Acta Neuropathologica (2022).

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