Project Details
Projekt
Regulation of neuronal proteostasis by the germline
Applicants
Hyun Ju Lee, Ph.D.; Professor Dr. David Vilchez
Subject Area
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 531902955
Misfolded and aggregated proteins challenge cellular integrity, leading to loss of cell function and viability. The accumulation of protein aggregates in neurons is a hallmark of age-related diseases such as Huntington’s, Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS). The late onset and heterogeneity of aggregates indicate that these neurodegenerative diseases are linked to converging cellular changes during aging. Indeed, post-mitotic cells such as neurons lose extensive control of the proteostasis equilibrium with age: widespread, aberrant changes in protein interactions, a loss of function in protein degradation machineries, and a generalized down regulation of chaperones often appear in somatic cells over time. Beyond intracellular changes, cumulative evidence indicates that proteostasis is also regulated by cell non-autonomous communication between tissues during aging. Thus, understanding cell non-autonomous mechanisms that modulate neuronal proteostasis is crucial to elucidate the links between aging and neurodegenerative diseases. In this proposal, our overarching goal is to define cell non-autonomous mechanisms regulated by the germline and assess their potential application for disease-related neurodegeneration. In previous work, we demonstrated that inducing proteostasis deficits in the germline of young animals triggers pathological aggregation of Huntington’s and ALS-related proteins in the neurons of C. elegans. However, the impact of aging on germline proteostasis and whether this tissue regulates pathological protein aggregation in distal tissues with age remains unknown. In Aim 1, we will determine age-associated changes in the intracellular proteostasis of germline cells and modulate these alterations to prevent protein aggregation in neuronal cells. Importantly, we have observed that cold temperature delays germline aging, and this process promotes somatic fitness and organismal longevity. Recently, we found that cold temperature also prevents disease-related protein aggregation in somatic tissues. In Aim 2, we will define how the signals and somatic changes triggered by a cold-induced rejuvenated germline prevent protein aggregation in the soma, thereby exploring the role of the germline-neuron axis in organismal proteostasis. Then, we will mimic these mechanisms in worm and human cell models at normal temperatures to assess their potential to prevent disease-related protein aggregation. Together, our research proposal can define cell non-autonomous pathways regulated by the germline with implications for disease intervention.
DFG Programme
Research Units
