Modulation of α‐crystallin chaperone activity: A target to prevent or delay cataract?

Pasupulati, Anil Kumar; Reddy, G. Bhanuprakash

doi:10.1002/iub.176

Cited by 47 publications

(46 citation statements)

References 102 publications

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“…The transparency of eye lens is maintained by the exquisite packing of lens proteins and chaperone-like activity of acrystallin (26,27). It is believed that oxidative stress, osmotic stress, and nonenzymatic glycation of lens proteins result in altered structural and functional integrity either due to direct modification and/or due to reduced a-crystallin chaperone activity, resulting in lens protein aggregation and thus opacification (13)(14)(15)28).…”

Section: Figmentioning

confidence: 99%

Increased risk of cataract development in WNIN‐obese rats due to accumulation of intralenticular sorbitol

et al. 2013

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Epidemiological studies have reported an association between obesity and increased incidence of ocular complications including cataract, yet the underlying biochemical and molecular mechanisms remained unclear. Previously we had demonstrated accumulation of sorbitol in the lens of obese rats (WNIN/Ob) and more so in a related strain with impaired glucose tolerance (WNIN/GR-Ob). However, only a few (15-20%) WNIN/Ob and WNIN/GR-Ob rats develop cataracts spontaneously with age. To gain further insights, we investigated the susceptibility of eye lens proteins of these obese rat strains to heat-and UV-induced aggregation in vitro, lens opacification upon glucose-mediated sorbitol accumulation ex vivo, and onset and progression of cataract was followed by galactose feeding and streptozotocin (STZ) injection. The results indicated increased susceptibility toward heat-or UV-induced aggregation of lens proteins in obese animals compared to their littermate lean controls. Further, in organ culture studies glucose-induced sorbitol accumulation was found to be higher and thus the lens opacification was faster in obese animals compared to their lean littermates. Also, the onset and progression of galactose-or STZ-induced cataractogenesis was faster in obese animals compared to lean control. These results together with our previous observations suggest that obesity status could lead to hyperaccumulation of sorbitol in eye lens, predisposing them to cataract, primarily by increasing their susceptibility to environmental and/or physiological factors. Further, intralenticular sorbitol accumulation beyond a threshold level could lead to cataract in WNIN/Ob and WNIN/ GR-Ob rats. V C 2013 IUBMB Life, 65(5): [472][473][474][475][476][477][478] 2013

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Section: Figmentioning

confidence: 99%

Increased risk of cataract development in WNIN‐obese rats due to accumulation of intralenticular sorbitol

et al. 2013

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“…With ageing, eye lens proteins undergo various post-translational modifications, which mostly lead to their aggregation. Various physiological, environmental, and genetic factors accelerate this aggregation and predispose the lens to cataract formation (10,17). Retinal degenerations (RD), a group of heterogeneous diseases of the retina, are characterized by photoreceptor degeneration and retinal pigment epithelium atrophy, causing loss of visual field and acuity, resulting in irreversible blindness (18).…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s and Danish dementia peptides induce cataract and perturb retinal architecture in rats

Reddy

Surolia

2017

Biomolecular Concepts

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Familial Danish dementias (FDDs) are autosomal dominant neurodegenerative disorders that are associated with visual defects. In some aspects, FDD is similar to Alzheimer's disease (AD)-the amyloid deposits in FDD and AD are made of short peptides: amyloid β (Aβ) in AD and ADan in FDD. Previously, we demonstrated an inter action between the dementia peptides and α-crystallin leading to lens opacification in organ culture due to impaired chaperone activity of α-crystallin. Herein, we report the in vivo effects of ADan and Aβ on the eye. ADan [reduced (ADan-red) and oxidized (ADan-oxi)] and Aβ (Aβ1-40 and Aβ1-42) were injected intravitreally in rats. The onset of cataract was seen after injection of all the peptides, but the cataract matured by 2 weeks in the case of ADan-red, 5 weeks for ADan-oxi and 6 weeks for Aβ1-40, while Aβ1-42 had minimal effect on cataract progression. The severity of cataract is associated with insolubilization and alterations in crystallins and loss of chaperone activity of α-crystallin. Further, disruption of the architecture of the retina was evident from a loss of rhodopsin, increased gliosis, and the thinning of the retina. These results provide a basis for the dominant heredo-otoophthalmo-encephalopathy (HOOE)/FDD syndrome and indicate that ADan peptides are more potent than Aβ peptides in inflicting visual impairment.

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“…Numerous independent cases of autosomal dominant cataract resulting from the R116C mutation have been described [132]. The R116C mutation is located in the conserved -crystallin domain and dramatically decreases the chaperone function of the protein [127]. Interactions of R116C HSPB4 with their natural substrates: -, -crystallins and actin were also reduced [131,133,134].…”

Section: Cataract and Desmin-related Myopathy -Proteinmisfolding Disementioning

confidence: 99%

“…In addition to -crystallin, the mammalian lens contains ß-and -crystallins which are constantly subjected to posttranslational modifications (acetylation, deamidation, phosphorylation, truncation, methylation and oxidation) from the beginning of lens development [127]. Since the eye lens is characterized by such a limited metabolism and lack of protein turnover, modified unfunctional proteins cannot be degraded and tend to form aggregates.…”

Section: Cataract and Desmin-related Myopathy -Proteinmisfolding Disementioning

confidence: 99%

Small Heat Shock Proteins and Protein-Misfolding Diseases

Laskowska

Matuszewska²,

Kuczyńska-Wiśnik

2010

CPB

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Small heat shock proteins (sHsps) are molecular chaperones ubiquitously distributed in numerous species, from bacteria to humans. A conserved C-terminal "alpha-crystallin" domain organized in a beta-sheet sandwich and oligomeric structure are common features of sHsps. sHsps protect cells against many kinds of stresses including heat shock, oxidative and osmotic stress. sHsps recognize unfolded proteins, prevent their irreversible aggregation and facilitate refolding of bound substrates in cooperation with ATP-dependent molecular chaperones (Hsp70/Hsp40). Mammalian sHsps (HSPBs) are multifunctional proteins involved in many cellular processes including those which are not directly related to protein folding and aggregation. HSPBs participate in cell development and cancerogenesis, regulate apoptosis and control cytoskeletal architecture. Recent data revealed that HSPBs also play an important role in membrane stabilization. Mutation in HSPB genes have been identified, which are responsible for the development of cataract, desmin related myopathy and neuropathies. HSPBs are often found as components of protein aggregates associated with protein-misfolding disorders, such as Parkinson's, Alzheimer's, Alexander's and prion diseases. It is supposed that the presence of HSPBs in intra- or extracellular protein deposits is a consequence of the chaperone activity of HSPBs, however more studies are needed to reveal the exact function of HSPBs during the formation (or removal) of disease-related aggregates.

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Modulation of α‐crystallin chaperone activity: A target to prevent or delay cataract?

Cited by 47 publications

References 102 publications

Increased risk of cataract development in WNIN‐obese rats due to accumulation of intralenticular sorbitol

Increased risk of cataract development in WNIN‐obese rats due to accumulation of intralenticular sorbitol

Alzheimer’s and Danish dementia peptides induce cataract and perturb retinal architecture in rats

Small Heat Shock Proteins and Protein-Misfolding Diseases

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