Clusterin: A forgotten player in Alzheimer's disease

Nuutinen, Tapio; Suuronen, Tiina; Kauppinen, Anu; Salminen, Antero

doi:10.1016/j.brainresrev.2009.05.007

Cited by 250 publications

(233 citation statements)

References 192 publications

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“…For example, its interaction with ␤-amyloid promotes ␤-amyloid clearance and uptake (via cell surface megalin receptor) and subsequent degradation (36). Recent association of single nucleotide polymorphisms at the CLU gene locus with Alzheimer disease (37,38) supports the suggestion that both CLU and APOE may act as modifying genes to cooperatively regulate the deposition and clearance of ␤-amyloid (39), which may affect the onset and/or clinical expression of the disease.…”

Section: Discussionmentioning

confidence: 97%

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Clusterin (Apolipoprotein J), a Molecular Chaperone That Facilitates Degradation of the Copper-ATPases ATP7A and ATP7B

Materia

Cater

Klomp

et al. 2011

Journal of Biological Chemistry

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The copper-transporting P 1B -type ATPases (Cu-ATPases) ATP7A and ATP7B are key regulators of physiological copper levels. They function to maintain intracellular copper homeostasis by delivering copper to secretory compartments and by trafficking toward the cell periphery to export excess copper. Mutations in the genes encoding ATP7A and ATP7B lead to copper deficiency and toxicity disorders, Menkes and Wilson diseases, respectively. This report describes the interaction between the Cu-ATPases and clusterin and demonstrates a chaperone-like role for clusterin in facilitating their degradation. Clusterin interacted with both ATP7A and ATP7B in mammalian cells. This interaction increased under conditions of oxidative stress and with mutations in ATP7B that led to its misfolding and mislocalization. A Wilson disease patient mutation (G85V) led to enhanced ATP7B turnover, which was further exacerbated when cells overexpressed clusterin. We demonstrated that clusterin-facilitated degradation of mutant ATP7B is likely to involve the lysosomal pathway. The knockdown and overexpression of clusterin increased and decreased, respectively, the Cu-ATPase-mediated copper export capacity of cells. These results highlight a new role for intracellular clusterin in mediating Cu-ATPase quality control and hence in the normal maintenance of copper homeostasis, and in promoting cell survival in the context of disease. Based on our findings, it is possible that variations in clusterin expression and function could contribute to the variable clinical expression of Menkes and Wilson diseases.

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Section: Discussionmentioning

confidence: 97%

“…The role of clusterin as an extracellular chaperone is well established (16,19,36). For example, its interaction with ␤-amyloid promotes ␤-amyloid clearance and uptake (via cell surface megalin receptor) and subsequent degradation (36).…”

Section: Discussionmentioning

confidence: 99%

Clusterin (Apolipoprotein J), a Molecular Chaperone That Facilitates Degradation of the Copper-ATPases ATP7A and ATP7B

Materia

Cater

Klomp

et al. 2011

Journal of Biological Chemistry

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“…29 Two recent large genome-wide association studies demonstrated that clusterin is an important susceptibility gene for late onset AD. 30,31 Indeed, clusterin has been found in the regions of the brain most affected in AD, the hippocampus and entorhinal cortex (for review see Nuutinen et al 32 ). However, clusterin is rarely found in neurons containing neurofibrillary tangles.…”

Section: Discussionmentioning

confidence: 99%

Clusterin secreted by astrocytes enhances neuronal differentiation from human neural precursor cells

Cordero-Llana

Scott²,

Maslen

et al. 2011

Cell Death Differ

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Neuronal differentiation from expanded human ventral mesencephalic neural precursor cells (NPCs) is very limited. Astrocytes are known to secrete neurotrophic factors, and so in order to enhance neuronal survival from NPCs, we tested the effect of regional astrocyte-conditioned medium (ACM) from the rat cortex, hippocampus and midbrain on this process. Human NPC's were expanded in FGF-2 before differentiation for 1 or 4 weeks in ACM. The results show that ACM from the hippocampus and midbrain increase the number of neurons from expanded human NPCs, an effect that was not observed with cortical ACM. In addition, both hippocampal and midbrain ACM increased the number and length of phosphorylated neurofilaments. MALDI-TOF analysis used to determine differences in media revealed that although all three regional ACMs had cystatin C, a-2 macroglobulin, extracellular matrix glycoprotein and vimentin, only hippocampal and midbrain ACM also contained clusterin, which when immunodepleted from midbrain ACM eliminated the observed effects on neuronal differentiation. Furthermore, clusterin is a highly glycosylated protein that has no effect on cell proliferation but decreases apoptotic nuclei and causes a sustained increase in phosphorylated extracellular signalregulated kinase, implicating its role in cell survival and differentiation. These findings further reveal differential effects of regional astrocytes on NPC behavior and identify clusterin as an important mediator of NPC-derived neuronal survival and differentiation. Cell Death and Differentiation (2011) 18, 907-913; doi:10.1038/cdd.2010.169; published online 7 January 2011Astrocytes are essential regulators of neuronal function, and produce diffusible and non-diffusible neuron supporting signals, including neurotrophic factors and membrane-bound molecules (for review see Barres 1 ). Interestingly, emerging evidence highlights that there are many regional differences in astrocytes in respect to structure and function and soluble factor production, for example, astrocytes from the hippocampus and their conditioned media can support the survival of neurons from regions other than the hippocampus. 2 In contrast, astrocytes from the mesencephalon release factors, which are more effective at promoting dopamine neuron survival than cortical or striatal astrocytes. 3 These studies show that the astrocytes from neurogenic regions 4 release more neurogenic factors than astrocytes from the non-neurogenic regions.It is well established that stem cells can be isolated from the developing and adult rodent CNS, and expanded in vitro using EGF and FGF2 (for review see Gage 5 ) More recently the same has been shown to be true for the developing human fetal CNS. 6 These cells are capable of long-term expansion in vitro to achieve B50 population doublings. 6 However, as they progress in culture with time, their differentiation pattern changes with the number of neurons declining and the number of astrocytes predominating. 7 Previous studies have shown that astrocyte-conditioned medi...

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“…During differentiation of PC12 cells, VCAM-1 was increased but not NCAM ( Figure 2C). Clusterin is a chaperone molecule and disulfide-linked heterodimeric protein which is implicated in many physiological processes such as programmed cell death, cell-cell adhesion, sperm maturation and tissue remodeling (Jones and Jomary 2002;Nuutinen et al 2009). It was reported that histone deacetylase inhibitors and 5-aza-2-deoxycytidine increase the expression of clusterin and secretion of clusterin proteins in neural cells (Nuutinen et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Butyrate-induced differentiation of PC12 cells to chromaffin cells involves cell adhesion and induction of extracellular proteins and cell adhesion proteins

Heoa

Kho

et al. 2010

Animal Cells and Systems

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PC12 cells were differentiated into the cells of chromaffin phenotype by butyrate treatment. Cells were aggregated and formed tight cell adhesion. To investigate the molecular change in this differentiation, we examined expression levels of cell adhesion proteins and extracellular proteins during butyrate induced-differentiation of PC12 cells. Integrin b1, integrin a7, E cadherin, VCAM, collagen-I, fibronectin, desmoglein and connexin were increased during differentiation. The levels of clusterin and secreted clusterin were also increased. These increased levels of cell adhesion proteins and extracellular proteins appear to induce cell aggregation and tight cell adhesion. The levels of p21, p27 and p16 were increased probably because of differentiation-related growth arrest during differentiation. Prolonged incubation of butyrate up to 1 day was required for differentiation. Signal transduction pathways for this differentiatiom could not be identified since various inhibitors had no effect. The results showed that butyrateinduced differentiation of PC12 cells to chromaffin cells involves tight cell adhesion and induction of extracellular proteins and cell adhesion proteins.

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Clusterin: A forgotten player in Alzheimer's disease

Cited by 250 publications

References 192 publications

Clusterin (Apolipoprotein J), a Molecular Chaperone That Facilitates Degradation of the Copper-ATPases ATP7A and ATP7B

Clusterin (Apolipoprotein J), a Molecular Chaperone That Facilitates Degradation of the Copper-ATPases ATP7A and ATP7B

Clusterin secreted by astrocytes enhances neuronal differentiation from human neural precursor cells

Butyrate-induced differentiation of PC12 cells to chromaffin cells involves cell adhesion and induction of extracellular proteins and cell adhesion proteins

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