Project Details
Projekt
Cell non-autonomous alterations of neuronal proteostasis in neurodegeneration
Applicant
Professorin Irina Dudanova, Ph.D.
Subject Area
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 531902955
Collapse of proteostasis is a crucial event in neurodegeneration, leading to accumulation and deposition of aggregated proteins in the brain. In all neurodegenerative diseases, the aggregates initially appear only in a limited population of neurons, then gradually spread to other populations and brain regions. How the formation of aggregates in the earliest-affected cells affects protein quality control in the neighboring and synaptically connected populations is not known. Moreover, recent findings have implemented glial cells in cell-to-cell propagation of pathology, but the role of neuron-glia interactions in disease-related proteostasis impairments remains poorly understood. In the proposed project, we will address these questions using neuronal co-culture models, as well as a new proteostasis reporter mouse generated by my laboratory. First, we will employ compartmentalized microfluidic chambers to dissect the mechanistic details of cell non-autonomous proteostasis responses in neurons. Second, using inducible tauopathy mice with precise spatiotemporal control of expression, we will target tau to specific populations of neurons or glia, and assess cell non-autonomous effects on the proteostasis of neighboring and remote neuronal populations with the proteostasis reporter. To uncover the underlying molecular mechanisms of intercellular proteostasis crosstalk, we will test two known proteins implicated in cell-to-cell propagation of tau. Furthermore, we will conduct proteomic analyses of the brain regions with proteostasis changes revealed by the reporter. The identified pathways will be validated in primary neurons and in co-cultures of neurons and glia derived from induced pluripotent stem cells (iPSCs) of patients with familial tau mutations. Taken together, these studies combining in vivo analyses in genetic mouse models with mechanistic cell culture approaches will shed new light on proteostasis mechanisms in neurodegeneration, and pinpoint potential new targets for diagnostic and disease-modifying strategies.
DFG Programme
Research Units
