期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 38, 期 20, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00011-18
关键词
Alzheimer's disease; CLN5; endosomes; NCL; retromer
资金
- National Institutes of Health [RF1AG054080, RF1AG015473, P50AG008702]
- NATIONAL INSTITUTE ON AGING [RF1AG015473, P50AG008702, RF1AG054080] Funding Source: NIH RePORTER
In a whole-exome sequencing study of multiplex Alzheimer's disease (AD) families, we investigated three neuronal ceroid lipofuscinosis genes that have been linked to retromer, an intracellular trafficking pathway associated with AD: ceroid lipofuscinosis 3 (CLN3), ceroid lipofuscinosis 5 (CLN5), and cathepsin D (CTSD). We identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD. We find that this variant causes glycosylation defects in the expressed protein, which causes it to be retained in the endoplasmic reticulum with reduced delivery to the endolysosomal compartment, CLN5's normal cellular location. The AD-associated CLN5 variant is shown here to reduce the normal processing of cathepsin D and to decrease levels of full-length amyloid precursor protein (APP), suggestive of a defect in retromer-dependent trafficking.
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