Protein complex may help prevent neurodegenerative diseases

Protein complex may help prevent neurodegenerative diseases

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.

Concepts Keywords
A40 Chaperone
Aging Spinocerebellar ataxia
Alzheimer Ataxin
Amino Acids Senescence
Amyloid Neuroscience
Ataxia Neurodegeneration
Brain Rare diseases
Chaperone Autosomal dominant disorders
Chaperones Neurological disorders
Esther Proteins
Eukaryotes Organ systems
Eukaryotic Branches of biology
Fair Dealing Plaques progressive dysfunction
Fitness Aggregation disease
Germany Cut
Huntingtin Aggregation neurodegenerative diseases
Huntington
Konstanz
Leeds
Mass Spectrometry
Molecular Chaperone
Neurodegenerative Diseases
Neurodegenerative Disorders
Patrick Knight
Peptide
Peptides
Polypeptide
Progressive
Ribosome
Ribosomes
Spinocerebellar Ataxia
Stanford
Substrate
Substrates
Suppressor
Toxicity
Vivo
Worm

Semantics

Type Source Name
gene UNIPROT MAGEE1
drug DRUGBANK Amino acids
disease MESH ataxia
gene UNIPROT PTPN5
gene UNIPROT FBN1
gene UNIPROT KCNK3
disease MESH development
gene UNIPROT ANP32B
gene UNIPROT TNFSF13
gene UNIPROT SRPX
gene UNIPROT PNN
gene UNIPROT SMIM10L2A
gene UNIPROT SMIM10L2B
gene UNIPROT FBXW7
disease MESH death
disease DOID spinocerebellar ataxia
pathway BSID Aging
disease MESH aging
pathway BSID Ribosome
gene UNIPROT XK
gene UNIPROT NLRP1
drug DRUGBANK Acetylcysteine
pathway BSID Neurodegenerative Diseases
disease MESH neurodegenerative diseases

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