Identification of novel extracellular chaperones

• Applicant: Dr. Della David
• Subject Area: Biochemistry ; Cell Biology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429529297

Aging is the main known risk factor for a variety of neurodegenerative diseases in which specific proteins accumulate as pathological aggregates. Recently, several studies with the nematode C. elegans, a widely used model organism for exploring aging, have demonstrated that irreversible protein aggregation does not only affect a few specific proteins associated with disease but also occurs during the normal aging process, causing part of the proteome to become highly insoluble with age. The discovery of inherent age-dependent protein aggregation gives us the unprecedented opportunity to dissect the molecular and cellular mechanisms that regulate protein aggregation during normal aging.In this prospective study, we will focus on identifying mechanisms relevant for maintaining extracellular protein homeostasis during aging. Extracellular protein aggregation underlies several devastating diseases such as Alzheimer’s disease and systemic amyloidosis. Despite our extensive knowledge of intracellular proteostasis, we know relatively little about the factors governing protein homeostasis in the extracellular space. Several secreted proteins become highly insoluble with age in C. elegans and we have developed the first C. elegans model to visualize extracellular protein aggregation. We have carried out an RNA interference screen targeting secreted factors and the current project aims to characterize the positives hits with the goal of identifying novel extracellular chaperones. In mammals, only a few extracellular chaperones have been identified. These chaperones act as ATP-independent holdases that bind to extracellular misfolded proteins including amyloid-β and promote their removal by macrophages. Among our 13 top candidates for extracellular regulators of protein aggregation, six have human orthologs and several of these have been identified in CSF. In Aim A, we will characterize the chaperone activity of these human orthologs using standard in vitro assays. In Aim B, we will evaluate whether novel human chaperones prevent amyloid-β aggregation in a transgenic mouse model. Overall this project will bring insight into how to improve extracellular proteostasis during aging and in neurodegenerative diseases. Ultimately, modulating levels of these novel extracellular chaperones could be a strategy to delay Alzheimer’s disease.

• DFG Programme: Research Grants