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Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons
Developmental Cell ( IF 10.7 ) Pub Date : 2024-10-16 , DOI: 10.1016/j.devcel.2024.09.023 Denethi Wijegunawardana, Asima Nayak, Sonali S. Vishal, Neha Venkatesh, Pallavi P. Gopal
Developmental Cell ( IF 10.7 ) Pub Date : 2024-10-16 , DOI: 10.1016/j.devcel.2024.09.023 Denethi Wijegunawardana, Asima Nayak, Sonali S. Vishal, Neha Venkatesh, Pallavi P. Gopal
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Altered RNA metabolism and misregulation of transactive response DNA-binding protein of 43 kDa (TDP-43), an essential RNA-binding protein (RBP), define amyotrophic lateral sclerosis (ALS). Intermediate-length polyglutamine (polyQ) expansions of Ataxin-2, a like-Sm (LSm) RBP, are associated with increased risk for ALS, but the underlying biological mechanisms remain unknown. Here, we studied the spatiotemporal dynamics and mRNA regulatory functions of TDP-43 and Ataxin-2 ribonucleoprotein (RNP) condensates in rodent (rat) primary cortical neurons and mouse motor neuron axons in vivo. We report that Ataxin-2 polyQ expansions aberrantly sequester TDP-43 within RNP condensates and disrupt both its motility along the axon and liquid-like properties. We provide evidence that Ataxin-2 governs motility and translation of neuronal RNP condensates and that Ataxin-2 polyQ expansions fundamentally perturb spatial localization of mRNA and suppress local translation. Overall, our results support a model in which Ataxin-2 polyQ expansions disrupt stability, localization, and/or translation of critical axonal and cytoskeletal mRNAs, particularly important for motor neuron integrity.
更新日期：2024-10-16
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