Abstract

Protein misfolding and aggregation are key features of nearly all age-related neurodegenerative diseases, which continue to present a major global health challenge. Molecular chaperones, a diverse group of proteins aiding proper protein folding, offer promising targets for preventing protein aggregation. However, the specific chaperones that keep proteins correctly folded in the brain and spinal cord remain poorly understood.
This research aims to elucidate the role of DNAJC7, a specific molecular chaperone implicated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neuron degeneration and TDP-43 protein aggregation. The project will investigate how DNAJC7 influences TDP-43 aggregation in neurons of the brain and spinal cord, considering TDP-43’s association with ALS, frontotemporal dementia, and age-related cognitive decline.

The study will explore whether DNAJC7 directly recognizes proteins aggregating in various neurodegenerative diseases using a range of systems, from test tube assays to human brain and spinal cord tissues from affected patients. Additionally, mouse models and human neurons derived from stem cells will be employed to assess the impact of DNAJC7 absence on TDP-43 aggregation. Finally, cutting-edge and high-throughput proteomics and CRISPR-based tools will also be used to understand DNAJC7’s functional role in neurons and to establish the chaperones that best prevent TDP-43 aggregation in neurons.

Successful completion of this research could position DNAJC7 and its co-factors as therapeutic target for combating various age-related neurodegenerative diseases.