Aberrant protein aggregation is a hallmark of many age-related diseases, yet little is known about whether proteins aggregate with age in a non-disease setting. Using a systematic proteomics approach, we identified several hundred proteins that become more insoluble with age in the multicellular organism Caenorhabditis elegans. These proteins are predicted to be significantly enriched in beta-sheets, which promote disease protein aggregation. Strikingly, these insoluble proteins are highly over-represented in aggregates found in human neurodegeneration. We examined several of these proteins in vivo and confirmed their propensity to aggregate with age. Different proteins aggregated in different tissues and cellular compartments. Protein insolubility and aggregation were significantly delayed or even halted by reduced insulin/IGF-1-signaling, which also slows aging. We found a significant overlap between proteins that become insoluble and proteins that influence lifespan and/or polyglutamine-repeat aggregation. Moreover, overexpressing one aggregating protein enhanced polyglutamine-repeat pathology. Together our findings indicate that widespread protein insolubility and aggregation is an inherent part of aging and that it may influence both lifespan and neurodegenerative disease.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919420 | PMC |
| http://dx.doi.org/10.1371/journal.pbio.1000450 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Lipid-induced condensate formation from the Alzheimer's Aβ peptide triggers amyloid aggregation.
Proc Natl Acad Sci U S A
January 2025
Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
The onset and development of Alzheimer's disease is linked to the accumulation of pathological aggregates formed from the normally monomeric amyloid-β peptide within the central nervous system. These Aβ aggregates are increasingly successfully targeted with clinical therapies at later stages of the disease, but the fundamental molecular steps in early stage disease that trigger the initial nucleation event leading to the conversion of monomeric Aβ peptide into pathological aggregates remain unknown. Here, we show that the Aβ peptide can form biomolecular condensates on lipid bilayers both in molecular assays and in living cells.
View Article and Find Full Text PDFDirect and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model.
J Fungi (Basel)
January 2025
Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative disorders sharing pathological and genetic features, including mutations in the gene. FUS is an RNA-binding protein that mislocalizes to the cytoplasm and aggregates in ALS/FTD. In a yeast model, FUS proteinopathy is connected to changes in the epigenome, including reductions in the levels of H3S10ph, H3K14ac, and H3K56ac.
View Article and Find Full Text PDFKey Role of Phosphorylation in Small Heat Shock Protein Regulation via Oligomeric Disaggregation and Functional Activation.
Cells
January 2025
Department of Ophthalmology & Visual Sciences, The University of Michigan, Ann Arbor, MI 48109, USA.
Heat shock proteins (HSPs) are essential molecular chaperones that protect cells by aiding in protein folding and preventing aggregation under stress conditions. Small heat shock proteins (sHSPs), which include members from HSPB1 to HSPB10, are particularly important for cellular stress responses. These proteins share a conserved α-crystallin domain (ACD) critical for their chaperone function, with flexible N- and C-terminal extensions that facilitate oligomer formation.
View Article and Find Full Text PDFE46K α-Synuclein Mutation Fails to Promote Neurite Outgrowth by Not Inducing Cdc42EP2 Expression, Unlike Wild-Type or A53T α-Synuclein in SK-N-SH Cells.
Brain Sci
December 2024
Department of Anatomy, College of Medicine, Inje University, Busan 47392, Republic of Korea.
Background/objectives: α-Synuclein (α-syn) protein is a major pathological agent of familial Parkinson's disease (PD), and its levels and aggregations determine neurotoxicity in PD pathogenesis. Although the pathophysiological functions of α-syn have been extensively studied, its biological functions remain elusive, and there are reports of wild-type (WT) α-syn and two missense mutations of α-syn (A30P and A53T) inducing protective neuritogenesis through neurite outgrowth. However, the function of another α-syn mutation, E46K, has not been fully elucidated.
View Article and Find Full Text PDFNeuroinflammation in the Post-Ischemic Brain in the Presence of Amyloid and Tau Protein.
Discov Med
January 2025
Department of Pathophysiology, Medical University of Lublin, 20-090 Lublin, Poland.
Ischemia-induced brain neurodegeneration is a leading cause of mortality and permanent disability worldwide, with no definitive cure. The development of neuroinflammation following ischemic events plays a dual role; it is essential for brain repair and homeostasis and can also exacerbate post-ischemic damage and worsen neurological outcomes. Neuroinflammation represents a complex process involving interactions between infiltrating immune cells from the bloodstream and resident immune cells within the affected brain regions.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!