Multivalent GU-rich oligonucleotides sequester TDP-43 in the nucleus by inducing high molecular weight RNP complexes

Zhang, Xi; Das, Tanuza; Chao, Tiffany F.; Trinh, Vickie; Carmen-Orozco, Rogger P.; Ling, Jonathan P.; Kalab, Petr; Hayes, Lindsey R.

doi:10.1016/j.isci.2024.110109

iScience

2024

DOI: 10.1016/j.isci.2024.110109

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Multivalent GU-rich oligonucleotides sequester TDP-43 in the nucleus by inducing high molecular weight RNP complexes

Xi Zhang,

Tanuza Das,

Tiffany F. Chao

et al.

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2024

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Molecular Visualization of Neuronal TDP43 PathologyIn Situ

Erwin,

Chang,

Fernandez

et al. 2024

Preprint

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Nuclear exclusion and cytoplasmic accumulation of the RNA-binding protein TDP43 are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite this, the origin and ultrastructure of cytosolic TDP43 deposits remain unknown. Accumulating evidence suggests that abnormal RNA homeostasis can drive pathological TDP43 mislocalization, enhancing RNA misprocessing due to loss of nuclear TDP43 and engendering a cycle that ends in cell death. Here, we show that adding small monovalent oligonucleotides successfully recapitulates pathological TDP43 mislocalization and aggregation in iPSC-derived neurons (iNeurons). By employing a multimodalin situcryo-correlative light and electron microscopy pipeline, we examine how RNA influences the localization and aggregation of TDP43 in near-native conditions. We find that mislocalized TDP43 forms ordered fibrils within lysosomes and autophagosomes in iNeurons as well as in patient tissue, and provide the first high-resolution snapshots of TDP43 aggregatesin situ. In so doing, we provide a cellular model for studying initial pathogenic events underlying ALS, FTLD, and related TDP43-proteinopathies.

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Molecular Visualization of Neuronal TDP43 PathologyIn Situ

Erwin,

Chang,

Fernandez

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

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Multivalent GU-rich oligonucleotides sequester TDP-43 in the nucleus by inducing high molecular weight RNP complexes

Cited by 1 publication

References 64 publications

Molecular Visualization of Neuronal TDP43 PathologyIn Situ

Molecular Visualization of Neuronal TDP43 PathologyIn Situ

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