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ALS-causing D169G mutation disrupts the ATP-binding capacity of TDP-43 RRM1 domain

Mei Dang1, Jianxing Song1

  • 1Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, 119260, Singapore.

Biochemical and Biophysical Research Communications
|February 3, 2020
PubMed

Insights

The D169G mutation in TDP-43 enhances cytotoxicity in neurodegenerative diseases like ALS and FTD by altering protein dynamics and disrupting ATP binding, despite not changing its structure.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • TDP-43 protein aggregation is a key marker in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
  • Most ALS-associated mutations are in the intrinsically disordered prion-like domain of TDP-43.
  • The D169G mutation in the RRM1 domain is unique as it doesn't alter crystal structure or stability, leaving its cytotoxic mechanism unclear.

Purpose of the Study:

  • To elucidate the mechanism by which the D169G mutation enhances TDP-43 cytotoxicity.
  • To investigate the dynamic and functional changes induced by the D169G mutation in the TDP-43 RRM1 domain.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy was employed to study the TDP-43 RRM1 domain with the D169G mutation.
  • Analysis focused on residue dynamics and ATP-binding capacity.

Main Results:

  • The D169G mutation induces significant dynamic changes in a cluster of residues within the RRM1 domain.
  • Unexpectedly, the D169G mutation impairs the ATP-binding capability of the RRM1 domain, despite the mutation site being distant from the ATP-binding pocket.

Conclusions:

  • The study proposes a mechanism where D169G-induced dynamic alterations and disrupted ATP binding contribute to TDP-43 cytotoxicity.
  • This highlights the critical role of ATP in neurodegenerative diseases and aging processes.
Keywords:
ALSATPAdenosine triphosphateAmyotrophic lateral sclerosisD169G mutationNMR spectroscopyRNA-recognition motifRRMTAR-DNA binding protein-43TDP-43

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