Reduced secreted clusterin as a mechanism for Alzheimer-associated CLU mutations

Bettens, Karolien; Vermeulen, Steven; Cauwenberghe, Caroline Van; Heeman, Bavo; Asselbergh, Bob; Robberecht, Caroline; Engelborghs, Sebastiaan; Vandenbulcke, Mathieu; Vandenberghe, Rik; Deyn, Peter Paul De; Cruts, Marc; Broeckhoven, Christine Van; Sleegers, Kristel

doi:10.1186/s13024-015-0024-9

Cited by 46 publications

(44 citation statements)

References 31 publications

(46 reference statements)

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“…With initial Aβ upregulation, clusterin accumulates intraneuronally (54) and promotes Aβ production through mechanisms such as BACE2-mediated β-cleavage. Consistent with this hypothesis, clusterin mutations identified in AD patients retain clusterin in the intracellular form (55). Hence, the role of clusterin in sporadic AD may be time/stage dependent.…”

Section: Discussionmentioning

confidence: 57%

BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis

Wang

Cai

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 57%

BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis

Wang

Cai

et al. 2019

JCI Insight

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“…We noted co-segregation of a rare CLU variant and dementia in an AD family (Fam-56). Even though rare non-synonymous and small insertion/ deletion variants have been reported to increase AD risk [58,59], the p.(Thr203Ile) variant is predictably not deleterious, but at present, we cannot exclude its possible role in AD risk.…”

Section: Discussionmentioning

confidence: 80%

Genetics of dementia in a Finnish cohort

et al. 2018

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Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHMP2B. Several other genes have also been linked to FTD or FTD with motor neuron disease. Here we describe a cohort of 60 Finnish families with possible inherited dementia. Our aim was to clarify the genetic background of dementia in this cohort by analysing both known dementia-associated genes (APOE, APP, C9ORF72, GRN, PSEN1 and PSEN2) and searching for rare or novel segregating variants with exome sequencing. C9orf72 repeat expansions were detected in 12 (20%) of the 60 families, including, in addition to FTD, a family with neuropathologically verified AD. Twelve families (10 with AD and 2 with FTD) with representative samples from affected and unaffected subjects and without C9orf72 expansions were selected for whole-exome sequencing. Exome sequencing did not reveal any variants that could be regarded unequivocally causative, but revealed potentially damaging variants in UNC13C and MARCH4.

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“…The CLU gene has been identified as an important risk locus for Alzheimer's disease. Functional analyses suggest reduced secretion of the CLU protein as the mode of action for three CLU coding mutations [73].…”

Section: Chaperone Activity and Proteinase Inhibitionmentioning

confidence: 99%

“…CLU concentration in cerebrospinal fluid is low compared to other bodily fluids, suggesting protective activity could be easily overwhelmed and that supplementation might be of therapeutic value in Alzheimer's disease [73].…”

Section: Chaperone Activity and Proteinase Inhibitionmentioning

confidence: 99%

“…This provides substantial cytoprotection, but depends on achieving a critical molar ratio of CLU to substrate [71]. As noted above, CLU concentration in cerebrospinal fluid is low, suggesting the levels could be easily overwhelmed in disease and that CLU supplementation might be of therapeutic value in Alzheimer's [73]. Considering the low level of CLU in mouse tears, the same argument might be made for dry eye.…”

Section: Ocular Surface Barrier Function In Dry Eye Diseasementioning

confidence: 99%

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Clusterin in the eye: An old dog with new tricks at the ocular surface

Fini

Bauskar

Jeong

et al. 2016

Experimental Eye Research

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, M. R. (2016). Clusterin in the eye: an old dog with new tricks at the ocular surface. Experimental Eye Research, Clusterin in the eye: an old dog with new tricks at the ocular surface AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had been demonstrated throughout the body, including in the eye. Its homeostatic activities in proteostasis, cytoprotection, and anti-inflammation have been well documented, however its roles in health and disease are still not well understood. CLU is prominent at fluid-tissue interfaces, and in 1996 it was demonstrated to be the most highly expressed transcript in the human cornea, the protein product being localized to the apical layers of the mucosal epithelia of the cornea and conjunctiva. CLU protein is also present in human tears. Using a preclinical mouse model for desiccating stress that mimics human dry eye disease, the authors recently demonstrated that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration in the tears. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to LGALS3 (galectin-3), a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. CLU depletion from the ocular surface epithelia is seen in a variety of inflammatory conditions in humans and mice that lead to squamous metaplasia and a keratinized epithelium. This suggests that CLU might have a specific role in maintaining mucosal epithelial differentiation, an idea that can now be tested using the mouse model for desiccating stress. Most excitingly, the new findings suggest that CLU could serve as a novel biotherapeutic for dry eye disease. Competing Interests: US patent 9,241,974 B2 entitled "Clusterin pharmaceuticals and treatment methods using the same" (inventors: MEF and SJ), assigned to the University of Southern California, is connected with this work. MEF holds a management position with Proteris Biotech, Inc., Pasadena, CA, which is developing Protearin for dry eye based on clusterin. MRW declares that he has no competing interests. Page 3 of 65 AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had bee...

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Reduced secreted clusterin as a mechanism for Alzheimer-associated CLU mutations

Cited by 46 publications

References 31 publications

BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis

BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis

Genetics of dementia in a Finnish cohort

Clusterin in the eye: An old dog with new tricks at the ocular surface

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