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Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43, drive ribonucleoprotein condensate transport

Denethi Wijegunawardana, Sonali S Vishal, Neha Venkatesh

    Biorxiv : the Preprint Server for Biology
    |February 13, 2023
    PubMed

    Insights

    Ataxin-2 expansions disrupt TDP-43 protein movement and RNA regulation in neurons, contributing to Amyotrophic lateral sclerosis (ALS) pathology. This impacts crucial gene expression for motor neuron health.

    Area of Science:

    • Neuroscience
    • Molecular Biology
    • Genetics

    Background:

    • Amyotrophic lateral sclerosis (ALS) is linked to RNA metabolism defects and TDP-43 protein mislocalization.
    • Ataxin-2, an RNA-binding protein (RBP) with polyglutamine (polyQ) expansions, is genetically linked to increased ALS risk.
    • Understanding the interaction between TDP-43 and Ataxin-2 is crucial for elucidating ALS pathogenesis.

    Approach:

    • Live-cell confocal imaging, photobleaching, and translation reporter assays were employed.
    • These techniques were used to investigate TDP-43/Ataxin-2 dynamics and function in rodent primary cortical neurons.
    • The study focused on localization, transport, and mRNA regulatory roles.

    Key Points:

    • Ataxin-2 polyQ expansions aberrantly sequester TDP-43 within ribonucleoprotein (RNP) condensates.
    • These expansions disrupt TDP-43 axonal transport dynamics and its RNP condensates' liquid-like properties.
    • Ataxin-2 polyQ expansions impair mRNA spatial localization and suppress local translation.

    Conclusions:

    • Ataxin-2 plays a critical role in regulating the motility and translation of neuronal RNP condensates.
    • Ataxin-2 polyQ expansions fundamentally perturb RNA localization and translation, impacting neuronal function.
    • These findings highlight detrimental effects on transcripts vital for axonal and cytoskeletal integrity in motor neurons.

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