التفاصيل البيبلوغرافية
| العنوان: |
Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-/3CTF (C99). |
| المؤلفون: |
Ying Jiang, Yutaka Sato, Eunju Im, Berg, Martin, Bordi, Matteo, Darji, Sandipkumar, Kumar, Asok, Mohan, Panaiyur S., Bandyopadhyay, Urmi, Diaz, Antonio, Cuervo, Ana Maria, Nixon, Ralph A. |
| المصدر: |
Journal of Neuroscience; 7/3/2019, Vol. 39 Issue 27, p5255-5268, 14p |
| مصطلحات موضوعية: |
DOWN syndrome, AMYLOID beta-protein precursor, RNA sequencing, CONGENITAL disorders, CATHEPSIN D |
| مستخلص: |
Lysosomal 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 ayndrome (trisomy 21), a neurodevelopmental disorder and form of early onset AD, requires the extra gene copy of amyloid precursor protein (APP) and is specifically mediated by the /3 cleaved carboxy terminal fragment of APP (APP-/3CTF, C99). In primary fibroblasts from individuals with 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) as a basis for slowed LC3 turnover and the inactivation of cathepsin D and other lysosomal hydrolases known to be unstable or less active when lysosomal pH is persistently elevated. Normalizing lysosome pH by delivering acidic nanoparticles to lysosomes ameliorated lysosomal deficits, whereas RNA sequencing analysis excluded a transcriptional contribution to hydrolase declines. Cortical neurons cultured from the Ts2 mouse model of DS exhibited lysosomal deficits similar to those in DS cells. Lowering APP expression with siRNA or BACE1 inhibition reversed cathepsin deficits in both fibroblasts and neurons. Deleting one Bacel allele from adult Ts2 mice had similar rescue effects in vivo. The modest elevation of endogenous APP-j8CTF needed to disrupt lysosomal function in DS is relevant to sporadic AD where APP-/3CTF, but not APP, is also elevated. Our results extend evidence that impaired lysosomal acidification drives progressive lysosomal failure in multiple forms of AD. [ABSTRACT FROM AUTHOR] |
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