GSE127880 Lysosomal dysfunction in Down syndrome is APP-dependent and mediated by APP- βCTF (C99)

Contributors : Ying Jiang ; Yutaka Sato ; Eunju Im ; Martin Berg ; Matteo Bordi ; Sandipkumar Darji ; Asok Kumar ; Panaiyur S Mohan ; Urmi Bandyopadhyay ; Antonio Diaz ; Ana M Cuervo ; Ralph A NixonSeries Type : Expression profiling by high throughput sequencing ; Third-party reanalysisOrganism : Homo sapiensLysosomal failure underlies pathogenesis of numerous congenital neurodegenerative disorders and is an early and progressive feature of Alzheimer ’s disease (AD) pathogenesis. Here, we report that lysosomal dysfunction in Down Syndrome (Trisomy 21) requires the extra gene copy of amyloid precursor protein (APP) and is mediated by the beta cleaved carboxy terminal fragment of APP (APP-βCTF, C99). In primary fibroblasts from individuals wit h Down Syndrome (DS), lysosomal degradation of autophagic and endocytic substrates is selectively impaired causing them to accumulate in enlarged autolysosomes/lysosomes. Direct measurements of lysosomal pH uncovered a significant elevation (0.6 units) associated with slowed LC3 turnover and the in activation of cathepsin D (CTSD) and other lysosomal hydrolases known to be unstable or less active when lysosomal pH is persistently elevated. RNA sequencing analysis excluded a transcriptional contribution to hydrolase declines. Normalizing lysosome pH by delivering acidic nanoparticles to lysos omes ameliorated lysosomal deficits, implicating pH elevation as their primary basis. Cortical neurons cultured from the Ts2 mouse m...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Third-party reanalysis Homo sapiens Source Type: research