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Investigating the neuronal function of a novel HNRNPA1 variant

Aperçu du projet

While significant efforts have been made worldwide, the development of an effective therapy to significantly slow or halt amyotrophic lateral sclerosis (ALS) progression has remained elusive. This is due in part to our incomplete understanding of the molecular mechanisms that lead to disease and a lack of validated biomarkers to diagnose and track disease progression. The discovery that the primarily nuclear RNA binding protein TDP-43 (TAR DNA binding protein 43) was accumulated in the cytoplasm in the neurons of most ALS patients [and nearly half of frontotemporal dementia (FTD) patients] put a sharp focus on RNA metabolism as a key pathogenic mechanism. There is a growing consensus that the loss of nuclear TDP-43 function drives disease via impacts on RNA metabolism. Indeed, nuclear TDP-43 depletion is sufficient to induce neuromuscular junction retraction and motor neuron loss in mice. We have published that nuclear TDP-43 represses the alternative splicing of HNRNPA1 (Heterogeneous nuclear ribonucleoprotein A1). Thus, HNRNPA1 alternative splicing is de-repressed in the ALS/FTD context leading to the accumulation of a longer isoform, termed hnRNP A1B, in the cytoplasm of ALS patient motor neurons. This isoform is identical to hnRNP A1 except for an additional 52 amino acids in the intrinsically disordered region. hnRNP A1B is highly conserved and HNRNPA1 mutations are causative for familial ALS and multisystem neuropathy (of which FTD is a feature). Indeed, 12 disease-causing mutations are now known, all of which impact hnRNP A1B (seven uniquely impact this isoform). Despite these points, and its initial description 30 years ago, the function of hnRNP A1B is unknown. In the mouse spinal cord, we have uncovered that hnRNP A1B is highly expressed during development, and then becomes progressively restricted to motor neurons during adulthood. Moreover, while hnRNP A1B is localized to the nucleus similar to hnRNP A1, it also has a prominent cytoplasmic pool. Unpublished proteomics data reveal proteins involved in axo-dendritic transport and local protein synthesis as high confidence interactors of hnRNP A1B. As RBP isoform usage is typically tightly controlled and often due to tissue-specific alternative splicing, we hypothesize that disturbances in HNRNPA1 isoform usage drives functional changes that contribute to neuronal vulnerability and/or neurodegeneration. This proposal explores HNRNPA1 isoform usage as a key response to physiological stress and explores the consequences of ALS-associated mutations on key neuronal processes. Knowledge gained here will be extremely relevant to the development of novel therapeutics and/or biomarkers. AIM 1: Determine the function of hnRNP A1B in mRNA trafficking. Given our unpublished histological and proteomics data, we will examine whether hnRNP A1B participates in mRNA trafficking in neurons, and how ALS-linked mutations may impact this function. AIM 2: Identify the role of hnRNP A1B in local translation. We will explore the contribution of hnRNP A1B to local protein synthesis in neurons. This aim will identify peptides whose translation is dependent on hnRNP A1B. AIM 3: Determine whether hnRNP A1B upregulation is a physiological response to injury/stimuli. Key elements in Aim 2 and 3 will be re-explored in the presence of ALS-relevant extrinsic cues, such as hyperexcitabilty and axonal injury, using both cultured neurons and mice.

Chef d'équipe

Christine Vande Velde , Université de Montréal

Membres de l'équipe

Marlene Oeffinger, Institut de Recherches Cliniques de Montréal, Université de Montréal

Partenaire et Donateurs

Projet en cours

Investigating the neuronal function of a novel HNRNPA1 variant

  • Type de programme

    Team grants

  • Domaine de recherche

    Neurodegeneration

  • Disease Area

    ALS FR

  • Compétition

    ALS Canada - Brain Canada Discovery Grants

  • Province

    Québec

  • Date de Début

    2022

  • Montant total du financement

    $125,000

  • Contribution Santé Canada

    $62,500

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1200, avenue McGill College, bureau 1600
Montréal, Québec H3B 4G7

+1 514 989-2989 info@braincanada.ca

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