Publication date: Apr 12, 2019
Credit: Karina Gense Researchers from the Universities of Konstanz (Germany), Leeds (U. K.) and Stanford (U. S.) have discovered that the nascent polypeptide-associated complex (NAC) prevents the aggregation of proteins associated with several neurodegenerative diseases.
The study, “Dual role of ribosome-binding domain of NAC as a potent suppressor of protein aggregation and aging-related proteinopathies,” is published in the journal Molecular Cell Numerous devastating neurodegenerative disorders in humans, such as Huntington’s and Alzheimer’s disease, as well as a disease known as spinocerebellar ataxia, are linked to specific cellular proteins that accumulate in cells.
The current paper is the first to demonstrate conclusively that NAC exerts chaperone activity off the ribosome toward structurally diverse substrates including polyglutamine (PolyQ)-containing proteins and Amyloid-β 40 (Aβ40) peptides.
Importantly, NAC suppresses PolyQ aggregation and enhances the organismal fitness in vivo, as tests with the animal model system C. elegans conducted by the University of Konstanz team led by Drs Martin Gamerdinger and Elke Deuerling, assisted by their co-workers Karina Gense, Nadine Sachs and Renate SchlcF6mer, show.
PolyQ analyses of neuronal mice cells carried out by Professor Judith Frydman at Stanford University and her team, including one of the first authors, Dr. Koning Shen, assisted by Rebecca Chan, revealed that a reduction of NAC caused catastrophic damage within cells producing toxic PolyQ proteins, providing further evidence of the crucial role NAC plays with regard to suppressing protein aggregation.
The international research team identified the positively charged ribosome-binding N-βNAC subunit (N-βNAC), which is merely 40 amino acids long, as the crucial NAC domain responsible for exerting chaperone activity off the ribosome.
“What this implies is that N-βNAC effectively fulfills a dual role: It is responsible for binding NAC to the ribosome and, off the ribosome, for inhibiting protein aggregation of PolyQ proteins. “
The Leeds team chemically linked NAC to two proteins it helps to protect from forming toxic aggregations in the cell, Ataxin-3 and Amyloid-β 40, which are associated with spinocerebellar ataxia and Alzheimer’s disease, respectively.
Dual role of ribosome-binding domain of NAC as a potent suppressor of protein aggregation and aging-related proteinopathies.