An Alzheimer's linked loss‐of‐function CLN5 variant impairs Cathepsin D maturation consistent with a retromer trafficking defect: Genetics/molecular genetics. (7th December 2020)

• Record Type: Journal Article
• Authors: Reitz, Christiane
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.041044
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: While lysosomal storage diseases (LSDs) typically have been regarded as causing neurodegeneration early in life, recent observations showed that genetic variants that cause one type of LSD, Gaucher's disease, can also cause Parkinson's disease, strongly suggesting that genes causing LSDs might also act as risk factors for other late‐onset neurodegenerative disorders, notably Alzheimer's disease (AD). Method: Capitalizing on data from a whole exome sequencing study of 31 multiplex Alzheimer's disease (AD) families, we examined a select group of genes ( CLN3, CLN5, CTSD ) that cause another LSD, Neuronal ceroid lipofuscinosis (NCL), because they have been directly or indirectly associated with retromer trafficking, a key pathological mechanism in AD. To validate variant(s) identified in these analyses, we turned to cell culture to determine whether they have deleterious effects on normal function. Finally, because all three genes converge on Cathepsin D, we tested whether the abnormal function caused by identified variant(s) would affect the normal processing of this protein. Result: We identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD in multiplex families. We demonstrated 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. We showed that this variant reduces the normal processing of Cathepsin D and decreases levels of full‐length APP, in line with a defect in retromer‐dependent trafficking. Conclusion: CLN5 is highly expressed in the brain, in particular in microglia. Retromer deficiency has been found in microglia of AD brains, but the mechanisms underlying this deficiency are unclear. While future studies expressing the identified CLN5 variant are required to further characterize its functional consequences, we postulate that it mediates its AD‐associated toxicity by affecting retromer function in microglia. Notably, independent supporting evidence for an etiologic overlap between NCL and AD comes from recent studies reporting a novel PSEN1 mutation in a family diagnosed with adult‐onset NCL (Dolzhanskaya et al. J Alzheimers Dis. 2014), and a recent whole‐exome sequencing study reporting a CLN13 ( CTSF; Cathepsin F) mutation in a kindred with early‐onset Alzheimer's disease (Bras et al., Neurobiol Aging. 2016).