Cellular Stress and Protein Misfolding During Aging

Basaiawmoit, Rajiv Vaid; Rattan, Suresh I. S.

doi:10.1007/978-1-60761-756-3_7

Cited by 27 publications

(24 citation statements)

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“…Regulation of protein biogenesis, folding, targeting, quality control and degradation must be orchestrated in response to rapidly changing intrinsic and extrinsic signals. In light of the dynamic network of processes required to maintain a functional proteome, it seems more appropriate to refer to the process of maintaining proteome fidelity as proteodynamics (Basaiawmoit & Rattan, ). A challenge to studying protein maintenance with aging and aging interventions is the complex and dynamic nature of the proteostatic network since it is difficult to simultaneously assay all components of the network.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation

Hamilton

Miller

2017

The Journal of Physiology

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Incomplete conclusion that mitochondrial protein synthesis rate is slower in the long-lived model Protein synthesis Protein synthesis ≥ Insightful conclusion that new mitochondrial proteins synthesized are allocated to maintaining/ replacing proteins in existing cells in the long-lived model Simultaneously measure mitochondrial protein synthesis and DNA Synthesis rate Protein synthesis Protein synthesis ≥ DNA synthesis DNA synthesis < Control mouse Long-lived mouse Measure mitochondrial protein synthesis rate only Control mouse Long-lived mouseAbstract Proteostasis is one of the seven "pillars of aging research" identified by the Trans-NIH Geroscience Initiative and loss of proteostasis is associated with aging and age-related chronic disease. Accumulated protein damage and resultant cellular dysfunction are consequences of limited protein repair systems and slowed protein turnover. When relatively high rates of protein turnover are maintained despite advancing age, damaged proteins are more quickly degraded and replaced, maintaining proteome fidelity. Therefore, maintenance of protein turnover represents an important proteostatic mechanism. However, measurement of protein synthesis without consideration for cell proliferation can result in an incomplete picture, devoid of information about how new proteins are being allocated. Simultaneous measurement of protein and DNA synthesis provides necessary mechanistic insight about proteins apportioned for newly proliferating cells versus for somatic maintenance. Using this approach with a number of murine models of slowed aging shows that, compared to controls, energetic resources are directed more toward somatic maintenance and proteostasis, and away from cell growth and proliferation. In particular, slowed aging models are associated with heightened mechanisms of mitochondrial proteostatic maintenance. Taking cell proliferation into account may explain the paradoxical findings that aging itself and slowed aging interventions can both be characterized by slower rates of protein synthesis. Abstract figure legendProteostasis is one of the seven 'pillars of ageing research' identified by the Trans-NIH Geroscience Initiative, and loss of proteostasis is associated with ageing and age-related chronic disease. Maintenance of protein turnover represents an important mechanism for preserving proteome fidelity. However, measurement of protein synthesis without consideration for cell proliferation can result in an incomplete picture, devoid of information about how new proteins are being allocated. Simultaneous measurement of protein and DNA synthesis provides critical insight about proteins apportioned for newly proliferating cells versus for somatic maintenance. Using this approach with murine models of slowed ageing shows that mitochondrial proteostatic maintenance is a characteristic shared among these slowed ageing models.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation

Hamilton

Miller

2017

The Journal of Physiology

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“…Aging is considered to be a stressor and is associated with the accumulation of misfolded proteins 44 . Given the key role of SGTA in protein processing and folding 1 , we were interested to determine if aging resulted in a more pronounced phenotype in Sgta -null animals.…”

Section: Resultsmentioning

confidence: 99%

Small Glutamine-Rich Tetratricopeptide Repeat-Containing Protein Alpha (SGTA) Ablation Limits Offspring Viability and Growth in Mice

Philp

Day

Butler

et al. 2016

Sci Rep

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Small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) has been implicated as a co-chaperone and regulator of androgen and growth hormone receptor (AR, GHR) signalling. We investigated the functional consequences of partial and full Sgta ablation in vivo using Cre-lox Sgta-null mice. Sgta+/− breeders generated viable Sgta−/− offspring, but at less than Mendelian expectancy. Sgta−/− breeders were subfertile with small litters and higher neonatal death (P < 0.02). Body size was significantly and proportionately smaller in male and female Sgta−/− (vs WT, Sgta+/− P < 0.001) from d19. Serum IGF-1 levels were genotype- and sex-dependent. Food intake, muscle and bone mass and adiposity were unchanged in Sgta−/−. Vital and sex organs had normal relative weight, morphology and histology, although certain androgen-sensitive measures such as penis and preputial size, and testis descent, were greater in Sgta−/−. Expression of AR and its targets remained largely unchanged, although AR localisation was genotype- and tissue-dependent. Generally expression of other TPR-containing proteins was unchanged. In conclusion, this thorough investigation of SGTA-null mutation reports a mild phenotype of reduced body size. The model’s full potential likely will be realised by genetic crosses with other models to interrogate the role of SGTA in the many diseases in which it has been implicated.

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“…This finding is consistent with previous work that demonstrated glycerolipid metabolism increases in the tissues of aged mice. 49 However, complementary metabolic profiling analyses would be required to exclude the possibility that age-related increases in protein misfolding lead to an increase in the degradation or intracellular accumulation of protein, 50 and a decrease in the protein to lipid ratio on the aged HCs.…”

Section: Resultsmentioning

confidence: 99%

Identifying Differentiation Stage of Individual Primary Hematopoietic Cells from Mouse Bone Marrow by Multivariate Analysis of TOF-Secondary Ion Mass Spectrometry Data

et al. 2012

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The ability to self-renew and differentiate into multiple types of blood and immune cells renders hematopoietic stem and progenitor cells (HSPCs) valuable for clinical treatment of hematopoietic pathologies and as models of stem cell differentiation for tissue engineering applications. To study directed HSC differentiation and identify the conditions that recreate the native bone marrow environment, combinatorial biomaterials that exhibit lateral variations in chemical and mechanical properties are employed. New experimental approaches are needed to facilitate correlating cell differentiation stage with location in the culture system. We demonstrate that multivariate analysis of time-of-flight secondary ion mass spectrometry (TOF-SIMS) data can be used to identify the differentiation state of individual hematopoietic cells (HCs) isolated from mouse bone marrow. Here, we identify primary HCs from three distinct stages of B cell lymphopoiesis at the single cell level: HSPCs, common lymphoid progenitors, and mature B cells. The differentiation state of individual HCs in a test set could be identified with a partial least squares discriminant analysis (PLS-DA) model that was constructed with calibration spectra from HCs of known differentiation status. The lowest error of identification was obtained when the intra-population spectral variation between the cells in the calibration and test sets was minimized. This approach complements the traditional methods that are used to identify HC differentiation stage. Further, the ability to gather mass spectrometry data from single HSCs cultured on graded biomaterial substrates may provide significant new insight into how HSPCs respond to extrinsic cues as well as the molecular changes that occur during cell differentiation.

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Cellular Stress and Protein Misfolding During Aging

Cited by 27 publications

References 50 publications

Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation

Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation

Small Glutamine-Rich Tetratricopeptide Repeat-Containing Protein Alpha (SGTA) Ablation Limits Offspring Viability and Growth in Mice

Identifying Differentiation Stage of Individual Primary Hematopoietic Cells from Mouse Bone Marrow by Multivariate Analysis of TOF-Secondary Ion Mass Spectrometry Data

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