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Molecular Visualization of Neuronal TDP43 Pathology In Situ.

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|September 4, 2024
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Summary
This summary is machine-generated.

Researchers modeled amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) by inducing TDP43 protein mislocalization in neurons. They discovered TDP43 forms ordered fibrils within cellular compartments, offering new insights into these neurodegenerative diseases.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Nuclear exclusion and cytoplasmic accumulation of TDP43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).
  • The precise origin and ultrastructure of these cytosolic TDP43 deposits remain largely unknown.
  • Aberrant RNA homeostasis is implicated in driving pathological TDP43 mislocalization, leading to RNA misprocessing and neuronal cell death.

Purpose of the Study:

  • To investigate the cellular and ultrastructural basis of TDP43 aggregation in neurodegenerative diseases.
  • To develop a cellular model recapitulating pathological TDP43 mislocalization and aggregation.
  • To examine the role of RNA in TDP43 localization and aggregation dynamics.

Main Methods:

  • Utilized induced pluripotent stem cell-derived neurons (iNeurons) to model TDP43 proteinopathies.
  • Employed a multimodal in situ cryo-correlative light and electron microscopy pipeline for high-resolution imaging.
  • Introduced small monovalent oligonucleotides to induce TDP43 mislocalization and aggregation.

Main Results:

  • Successfully recapitulated pathological TDP43 mislocalization and aggregation in iNeurons by adding small oligonucleotides.
  • Observed that mislocalized TDP43 forms ordered fibrils within lysosomes and autophagosomes.
  • Provided the first high-resolution in situ images of TDP43 aggregates in both cellular models and patient tissue.

Conclusions:

  • Established a cellular model for studying the initial pathogenic events in ALS, FTLD, and related TDP43-proteinopathies.
  • Demonstrated that TDP43 forms ordered fibrils within lysosomes and autophagosomes under pathological conditions.
  • Highlighted the potential role of RNA in influencing TDP43 aggregation and cellular localization.