THE METASTABILITY OF PROTEOME FOLDEDNESS IN NEURODEGENERATIVE DISEASE
Grant number: 1161803 | Funding period: 2019 - 2023
Proteins are used by cells to control almost all their functions. A key feature of neurodegenerative diseases, like Alzheimer’s and Huntington’s is that certain proteins abnormally aggregate together which interferes with biological function. This grant seeks to understand why this happens and what the implications are for cellular survival. Gaining this knowledge will aid in the design of therapies combat this abnormality or prevent the damage that is caused by it.
Related publications (15)
Arginine-rich C9ORF72 ALS proteins stall ribosomes in a manner distinct from a canonical ribosome-associated quality control substrate.
Viacheslav Kriachkov, Angelique R Ormsby, Eric P Kusnadi, Hamish EG McWilliam, Justine D Mintern, Shanika L Amarasinghe, Matthew E Ritchie, Luc Furic, Danny M Hatters
Hexanucleotide expansion mutations in C9ORF72 are a frequent cause of amyotrophic lateral sclerosis. We previously reported that l..
Protein painting reveals pervasive remodeling of conserved proteostasis machinery in response to pharmacological stimuli
Dezerae Cox, Angelique R Ormsby, Gavin E Reid, Danny M Hatters
The correct spatio-temporal organization of the proteome is essential for cellular homeostasis. However, a detailed mechanistic un..
Sequence grammar underlying the unfolding and phase separation of globular proteins
Kiersten M Ruff, Yoon Hee Choi, Dezerae Cox, Angelique R Ormsby, Yoochan Myung, David B Ascher, Sheena E Radford, Rohit V. Pappu, Danny M Hatters
Aberrant phase separation of globular proteins is associated with many diseases. Here, we use a model protein system to understand..
Development and application of Diels-Alder adducts displaying AIE properties
Timothy L Gialelis, Tze Cin Owyong, Siyang Ding, Wenyi Li, Maoxing Yu, Neil M O'Brien-Simpson, Zujin Zhao, Jonathan M White, Bicheng Yao, Yuning Hong
Exploring organic reactions to construct novel molecules with aggregation-induced emission (AIE) features is an essential branch o..
Immiscible inclusion bodies formed by polyglutamine and poly(glycine-alanine) are enriched with distinct proteomes but converge in proteins that are risk factors for disease and involved in protein degradation
Mona Radwan, Jordan D Lilley, Ching-Seng Ang, Gavin E Reid, Danny M Hatters
Poly(glycine-alanine) (polyGA) is one of the polydipeptides expressed in Frontotemporal Dementia and/or Amyotrophic Lateral Sclero..
Nascent mutant Huntingtin exon 1 chains do not stall on ribosomes during translation but aggregates do recruit machinery involved in ribosome quality control and RNA
Angelique R Ormsby, Dezerae Cox, James Daly, David Priest, Elizabeth Hinde, Danny M Hatters
Mutations that cause Huntington's Disease involve a polyglutamine (polyQ) sequence expansion beyond 35 repeats in exon 1 of Huntin..
A Molecular Chameleon for Mapping Subcellular Polarity in an Unfolded Proteome Environment
Tze Cin Owyong, Pramod Subedi, Jieru Deng, Elizabeth Hinde, Jason J Paxman, Jonathan M White, Weisan Chen, Begona Heras, Wallace WH Wong, Yuning Hong
Environmental polarity is an important factor that drives biomolecular interactions to regulate cell function. Herein, a general m..
Arginine in C9ORF72 Dipolypeptides Mediates Promiscuous Proteome Binding and Multiple Modes of Toxicity
Mona Radwan, Ching-Seng Ang, Angelique R Ormsby, Dezerae Cox, James C Daly, Gavin E Reid, Danny M Hatters
C9ORF72-associated Motor Neuron Disease patients feature abnormal expression of 5 dipeptide repeat (DPR) polymers. Here we used qu..
Widespread remodeling of proteome solubility in response to different protein homeostasis stresses
Xiaojing Sui, Douglas EV Pires, Angelique R Ormsby, Dezerae Cox, Shuai Nie, Giulia Vecchi, Michele Vendruscolo, David B Ascher, Gavin E Reid, Danny M Hatters
The accumulation of protein deposits in neurodegenerative diseases has been hypothesized to depend on a metastable subproteome vul..
Modest Declines in Proteome Quality Impair Hematopoietic Stem Cell Self-Renewal
Lorena Hidalgo San Jose, Mary Jean Sunshine, Christopher H Dillingham, Bernadette A Chua, Miriama Kruta, Yuning Hong, Danny M Hatters, Robert AJ Signer
Low protein synthesis is a feature of somatic stem cells that promotes regeneration in multiple tissues. Modest increases in prote..