Proteostasis and Unfolded Protein Response Dynamics in Human Neuron and Mouse Glia Co-culture Reveal Cell-Specific Aging Responses.

Proteostasis, or protein homeostasis, is a tightly regulated network of cellular pathways essential for maintaining proper protein folding, trafficking, and degradation. Neurons are particularly vulnerable to proteostasis collapse due to their post-mitotic and long-lived nature and thus represent a unique cell type to understand the dynamics of proteostasis throughout development, maturation, and aging. Here, we utilized a dual-species co-culture model of human excitatory neurons and mouse glia to investigate cell type-specific, age-related changes in the proteostasis network using data-independent acquisition (DIA) LC-MS/MS proteomics.

Mitochondrial dysfunction mediated by ER-calcium dysregulation in neurons derived from Alzheimer's disease patients.

Tight regulation of mitochondrial Ca is essential for neuronal bioenergetics and cellular metabolism. Ca transfer from ER-localized ryanodine receptors (RyR) and inositol triphosphate receptors (IPR) to the mitochondria maintains a steady Ca source that fuels oxidative phosphorylation and ATP production. In Alzheimer's disease (AD), RyR-evoked Ca release is markedly increased, contributing to synaptic deficits, protein mishandling, and memory impairment.