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Developmental Biology - Molecular Biophysics

Preventing Protein Aggregates in The Brain

NAC prevents protein aggregation which leads to neurodegenerative disease...


Researchers from the Universities of Konstanz (Germany), Leeds (UK) and Stanford (USA) have discovered that growing polypeptide-associated complex (NAC) helps prevent aggregation of proteins in neurodegenerative diseases. Devastating neurodegenerative disorders, such as Huntington's and Alzheimer's disease as well as spinocerebellar ataxia, are linked to specific cell proteins accumulating in brain neurons. Such proteins form damaging plaques causing progressive dysfunction and death to these neurons.
A key chaperone of molecular cell structures is NAC, a protein complex found in all eukaryotes and required for healthy cell activity. NAC binds to ribosomes inside a cell to facilitate production of new proteins. Only now is its additional role in preventing cell degeneration understood, through its affect beyond the ribosome.

According to Elke Deuerling, Professor for Molecular Microbiology at the University of Konstanz and one of the lead authors on the study published in the journal Molecular Cell: "What is so fascinating is that NAC can recognise different types of aggregation-prone proteins and prevent them from aggregating. It is a very abundant cell protein and seems to be involved in many processes maintaining cell fitness, health and functionality. We believe it to be one of the most important chaperones in a cell."

NAC occurs in all eukaryotes from yeast to humans and was first described over 25 years ago. However its precise functions, though vital to the survival of organisms, have largely been unstudied. This paper is the first to conclusively demonstrate how NAC exerts chaperone activity off the ribosome and toward structural substrates like polyglutamine or PolyQ containing proteins and Amyloid-▀ 40 (A▀40) peptides. Importantly, NAC suppresses PolyQ aggregation, thus enhancing cell fitness in a living organism, as shown in C. elegans worms. This research was conducted by the University of Konstanz, Germany team.

PolyQ analyses of mouse neuron cells was carried out by Professor Judith Frydman at Stanford University, USA, and her team. Their work revealed that a reduction of NAC caused catastrophic damage within neuronal cells producing toxic PolyQ proteins. Further evidence of the crucial role NAC plays in suppressing protein aggregation.
The international research team identified positive charged ribosome-binding N-▀NAC subunit (N-▀NAC), a mere 40 amino acids long, as the crucial NAC domain responsible for exerting chaperone activity off the ribosome.

The Stanford team demonstrated how a small peptide within this sequence can successfully prevent aggregation of disease-linked polyglutamine-expanded proteins which include Huntingtin Ś causing Huntington's disease; and Ataxin-3, causing a form of ataxia. "This came as a huge surprise", comments Martin Gamerdinger of the Konstanz group. "What this implies is that N-▀NAC effectively fulfils a dual role: (1) It is responsible for binding NAC to the ribosome and, (2) off the ribosome, for inhibiting protein aggregation of PolyQ proteins."

NAC Graphical Abstract

An important contribution was made by Professor Sheena Radford and her team from Leeds, UK. Her team chemically linked NAC to two proteins it helps protect from forming toxic aggregations, Ataxin-3 and Amyloid-▀ 40. Both are associated with spinocerebellar ataxia and Alzheimer's disease, respectively.

Mass spectrometry was then used to find which precise parts of the chaperone and proteins were linked together. Results were clear cut and surprising.

Explains Professor Sheena Radford: "We found one specific region of NAC chaperone binds Ataxin-3 and when added in isolation, is sufficient to inhibit PolyQ aggregation. However, looking at Amyloid-▀ 40, we found at least one more chaperone domain within NAC that we have yet to uncover. We can clearly see the effects this domain has - it completely suppresses protein aggregation in both cases. But, we have not been able to identify this second binding site for Amyloid-▀ 40 yet."
"A future task for research will be identifying these unknown NAC substrate interaction domains. Another will be to apply study results into medical application."

Sheena Radford PhD, biophysicist, Astbury Professor of Biophysics, Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, UK.

"Being able to clearly identify one important chaperone domain within NAC has huge implications for the development of therapeutic approaches to combat neurodegenerative disorders," says Professor Judith Frydman. "Increasing concentration of NAC in cells to suppress protein aggregation Ś isn't universally beneficial. But, being able to work with small NAC fragment N-▀NAC - or with smaller peptides only 20 amino acids long we used to identify N-▀NAC - could be a game changer. We may not be able to cure diseases such as Huntington's or Alzheimer's any time soon, but we may be able to delay their progress."

Highlights
Ľ The protein biogenesis factor NAC exhibits broad-spectrum chaperone activity
Ľ NAC exerts a ribosome-independent chaperone function
Ľ The positively charged N terminus of ?NAC is a central chaperone entity of NAC
Ľ NAC suppresses aggregation and toxicity of disease-related polyglutamine proteins.

Summary
The nascent polypeptide-associated complex (NAC) is a conserved ribosome-associated protein biogenesis factor. Whether NAC exerts chaperone activity and whether this function is restricted to de novo protein synthesis is unknown. Here, we demonstrate NAC directly exerts chaperone activity toward structurally diverse model substrates including polyglutamine (PolyQ) proteins, firefly luciferase, and A?40. Strikingly, we identified the positively charged ribosome-binding domain in the N terminus of the ▀NAC subunit (N-▀NAC) as a major chaperone entity of NAC. N-▀NAC by itself suppressed aggregation of PolyQ-expanded proteins in vitro, and the positive charge of this domain was critical for this activity. Moreover, we found that NAC also exerts a ribosome-independent chaperone function in vivo. Consistently, we found that a substantial fraction of NAC is non-ribosomal bound in higher eukaryotes. In sum, NAC is a potent suppressor of aggregation and proteotoxicity of mutant PolyQ-expanded proteins associated with human diseases like Huntington's disease and spinocerebellar ataxias.

Authors
Koning Shen, Martin Gamerdinger, Rebecca Chan, Karina Gense, Esther M. Martin, Nadine Sachs, Patrick D. Knight, Renate Schl÷mer, Antonio N. Calabrese, Katie L. Stewart, Lukas Leiendecker, Ankit Baghel, Sheena E. Radford, Judith Frydman and Elke Deuerling.

Acknowledgements
Supported by research grants from the German Research Foundation (DFG), the Human Frontier Science Program (HFSP), the German state of Baden-WŘrttemberg (Professor Judith Frydman's guest professorship at the University of Konstanz), the Wellcome Trust, the European Research Council (ERC) under the European Union's Seventh Framework Programme, the Biotechnology and Biological Sciences Research Council UK (BBSRC) as well as the National Institutes of Health (NIH).

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Aug 7 2019   Fetal Timeline   Maternal Timeline   News  




(LEFT) Aggregation of PolyQ35 protein in C. elegans is suppressed by NAC. These images show the head region of c. elegans worms with a Huntington's disease protein (PolyQ35). (RIGHT) Over expression (function) of NAC in the worm prevents aggregation and toxicity by PolyQ35.
The positively charged ribosome-binding domain of NAC (N-▀NAC) suppresses protein
aggregation and proteotoxicity of polyglutamine (PolyQ) proteins.
CREDIT Karina Gense


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