Dataset Information

TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis.

ABSTRACT: See Fratta and Isaacs (doi:10.1093/brain/awy091) for a scientific commentary on this article.The RNA binding proteins TDP-43 (encoded by TARDBP) and hnRNP A1 (HNRNPA1) are each mutated in certain amyotrophic lateral sclerosis cases and are often mislocalized in cytoplasmic aggregates within motor neurons of affected patients. Cytoplasmic inclusions of TDP-43, which are accompanied by a depletion of nuclear TDP-43, are observed in most amyotrophic lateral sclerosis cases and nearly half of frontotemporal dementia cases. Here, we report that TDP-43 binds HNRNPA1 pre-mRNA and modulates its splicing, and that depletion of nuclear TDP-43 results in increased inclusion of a cassette exon in the HNRNPA1 transcript, and consequently elevated protein levels of an isoform containing an elongated prion-like domain, referred to as hnRNP A1B. Combined in vivo and in vitro approaches demonstrated greater fibrillization propensity for hnRNP A1B, which drives protein aggregation and is toxic to cells. Moreover, amyotrophic lateral sclerosis patients with documented TDP-43 pathology showed neuronal hnRNP A1B cytoplasmic accumulation, indicating that TDP-43 mislocalization may contribute to neuronal vulnerability and loss via altered HNRNPA1 pre-mRNA splicing and function. Given that TDP-43 and hnRNP A1 each bind, and thus modulate, a third of the transcriptome, our data suggest a much broader disruption in RNA metabolism than previously considered.

SUBMITTER: Deshaies JE

PROVIDER: S-EPMC5917749 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis.

Deshaies Jade-Emmanuelle JE Shkreta Lulzim L Moszczynski Alexander J AJ Sidibé Hadjara H Semmler Sabrina S Fouillen Aurélien A Bennett Estelle R ER Bekenstein Uriya U Destroismaisons Laurie L Toutant Johanne J Delmotte Quentin Q Volkening Kathryn K Stabile Stéphanie S Aulas Anaïs A Khalfallah Yousra Y Soreq Hermona H Nanci Antonio A Strong Michael J MJ Chabot Benoit B Vande Velde Christine C

Brain : a journal of neurology 20180501 5

See Fratta and Isaacs (doi:10.1093/brain/awy091) for a scientific commentary on this article.The RNA binding proteins TDP-43 (encoded by TARDBP) and hnRNP A1 (HNRNPA1) are each mutated in certain amyotrophic lateral sclerosis cases and are often mislocalized in cytoplasmic aggregates within motor neurons of affected patients. Cytoplasmic inclusions of TDP-43, which are accompanied by a depletion of nuclear TDP-43, are observed in most amyotrophic lateral sclerosis cases and nearly half of fronto ...[more]

PMID: 29562314

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Project description:Many of the molecular mechanisms underlying the pathological aggregation of proteins observed in neurodegenerative diseases are still not fully understood. Among the aggregate-associated diseases, Amyotrophic Lateral Sclerosis (ALS) is of relevant importance. In fact, although understanding the processes that cause the disease is still an open challenge, its relationship with protein aggregation is widely known. In particular, human TDP-43, an RNA/DNA binding protein, is a major component of the pathological cytoplasmic inclusions observed in ALS patients. Indeed, the deposition of the phosphorylated full-length TDP-43 in spinal cord cells has been widely studied. Moreover, it has also been shown that the brain cortex presents an accumulation of phosphorylated C-terminal fragments (CTFs). Even if it is debated whether the aggregation of CTFs represents a primary cause of ALS, it is a hallmark of TDP-43 related neurodegeneration in the brain. Here, we investigate the CTFs aggregation process, providing a computational model of interaction based on the evaluation of shape complementarity at the molecular interfaces. To this end, extensive Molecular Dynamics (MD) simulations were conducted for different types of protein fragments, with the aim of exploring the equilibrium conformations. Adopting a newly developed approach based on Zernike polynomials, able to find complementary regions in the molecular surface, we sampled a large set of solvent-exposed portions of CTFs structures as obtained from MD simulations. Our analysis proposes and assesses a set of possible association mechanisms between the CTFs, which could drive the aggregation process of the CTFs. To further evaluate the structural details of such associations, we perform molecular docking and additional MD simulations to propose possible complexes and assess their stability, focusing on complexes whose interacting regions are both characterized by a high shape complementarity and involve β3 and β5 strands at their interfaces.

Dataset Information

TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis.

Publications

TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis.

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