Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer's disease.

ABSTRACT: Impairments in neural lysosomal- and autophagic-mediated degradation of cellular debris contribute to neuritic dystrophy and synaptic loss. While these are well-characterized features of neurodegenerative disorders such as Alzheimer's disease (AD), the upstream cellular processes driving deficits in pathogenic protein mishandling are less understood. Using a series of fluorescent biosensors and optical imaging in model cells, AD mouse models and human neurons derived from AD patients, we reveal a previously undescribed cellular signaling cascade underlying protein mishandling mediated by intracellular calcium dysregulation, an early component of AD pathogenesis. Increased Ca²⁺ release via the endoplasmic reticulum (ER)-resident ryanodine receptor (RyR) is associated with reduced

SUBMITTER: Mustaly-Kalimi S 

PROVIDER: S-EPMC9894236 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature