Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy
L. M. DorschMaike SchuldtCristobal G. dos RemediosArend F. L. SchinkelPeter L. de JongMichelle MichelsDiederik W.D. KusterBianca J.J.M. BrundelJolanda van der Velden
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Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder. It is mainly caused by mutations in genes encoding sarcomere proteins. Mutant forms of these highly abundant proteins likely stress the protein quality control (PQC) system of cardiomyocytes. The PQC system, together with a functional microtubule network, maintains proteostasis. We compared left ventricular (LV) tissue of nine donors (controls) with 38 sarcomere mutation-positive (HCMSMP) and 14 sarcomere mutation-negative (HCMSMN) patients to define HCM and mutation-specific changes in PQC. Mutations in HCMSMP result in poison polypeptides or reduced protein levels (haploinsufficiency, HI). The main findings were 1) several key PQC players were more abundant in HCM compared to controls, 2) after correction for sex and age, stabilizing heat shock protein (HSP)B1, and refolding, HSPD1 and HSPA2 were increased in HCMSMP compared to controls, 3) α-tubulin and acetylated α-tubulin levels were higher in HCM compared to controls, especially in HCMHI, 4) myosin-binding protein-C (cMyBP-C) levels were inversely correlated with α-tubulin, and 5) α-tubulin levels correlated with acetylated α-tubulin and HSPs. Overall, carrying a mutation affects PQC and α-tubulin acetylation. The haploinsufficiency of cMyBP-C may trigger HSPs and α-tubulin acetylation. Our study indicates that proliferation of the microtubular network may represent a novel pathomechanism in cMyBP-C haploinsufficiency-mediated HCM.Keywords:
Haploinsufficiency
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Abstract Floating‐Harbor syndrome (FHS) is characterized by characteristic facial dysmorphism, short stature with delayed bone age, and expressive language delay. To date, the gene(s) responsible for FHS is (are) unknown and the diagnosis is only made on the basis of the clinical phenotype. The majority of cases appeared to be sporadic but rare cases following autosomal dominant inheritance have been reported. We identified a 4.7 Mb de novo 12q15‐q21.1 microdeletion in a patient with FHS and intellectual deficiency. Pangenomic 244K array‐CGH performed in a series of 12 patients with FHS failed to identify overlapping deletions. We hypothesized that FHS is caused by haploinsufficiency of one of the 19 genes or predictions located in the deletion found in our index patient. Since none of them appeared to be good candidate gene by their function, a high‐throughput sequencing approach of the region of interest was used in eight FHS patients. No pathogenic mutation was found in these patients. This approach failed to identify the gene responsible for FHS, and this can be explained by at least four reasons: (i) our index patient could be a phenocopy of FHS; (ii) the disease may be clinically heterogeneous (since the diagnosis relies exclusively on clinical features), (iii) these could be genetic heterogeneity of the disease, (iv) the patient could carry a mutation in a gene located elsewhere. Recent descriptions of patients with 12q15‐q21.1 microdeletions argue in favor of the phenocopy hypothesis. © 2012 Wiley Periodicals, Inc.
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Preclinical models of neurodevelopmental disorders typically use single inbred strains which fail to capture human genetic and symptom heterogeneity that is common clinically. We tested if systematically modeling human genetic diversity in mouse genetic reference panels would recapitulate population and individual differences in responses to a syndromic mutation in the high-confidence autism risk gene, Chd8. Trait disruptions mimicked those seen in human populations, including high penetrance of macrocephaly and disrupted behavior, but with robust strain and sex differences. For every trait, some strains exhibited a range of large effect size disruptions, sometimes in opposite directions, and remarkably others expressed resilience. Thus, systematically introducing genetic diversity into mouse models of neurodevelopmental disorders provides a better framework for discovering individual differences in symptom etiologies and improved treatments.Funding Information: National Institute of Mental Health grant R21MH118685 (P.L., A.K.) National Science Foundation Postdoctoral Research Fellowship in Biology grant 2011039 (M.T.), The Saban Research Institute Research Career Development Fellowship (M.T.), Simms Mann Chair in Developmental Neurogenetics and Developmental Neuroscience and Neurogenetics Program, Children’s Hospital Los Angeles (P.L.), and WM Keck Chair in Neurogenetics, Keck School of Medicine of the University of Southern California (P.L.).Declaration of Interests: Authors declare that they have no competing interests.Ethics Approval Statement: All experimental procedures were approved by the University of Southern California (USC) Institutional Animal Care and Use Committee under protocol 11844-CR011. In addition, all experimental procedures followed the Guidelines for the Care and Use of Laboratory Animals by the National Institutes of Health.
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A total of 1.67 million breast cancer cases per year are reported worldwide. Of these, 5%-10% are caused by inherited mutations. Phenocopy is a rare phenomenon, with only a few cases reported in the literature. In phenocopies, phenotypes identical to those with genetic origin occur because of environmental factors rather than familial mutations. We describe a case of phenocopy in a 44-year-old female patient with triple-negative breast cancer. The mother and sister wee heterozygous for c.1813delA, p.Ile605TyrfsTer9 in BRCA2 . The patient underwent genetic testing for BRCA1 and BRCA2 and exome sequencing. Familial or other cancer variants were not detected. The most accepted phenocopy theory is that patients without genetic variants but who are carriers of these mutations undergo cellular changes due to environmental factors, increasing the risk of breast cancer. Therefore, the detection of phenocopy in patients with breast cancer is important in clinical practice.
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Aging is a complex process regulated by multiple cellular pathways, including the proteostasis network. The proteostasis network consists of molecular chaperones, stress-response transcription factors, and protein degradation machines that sense and respond to proteotoxic stress and protein misfolding to ensure cell viability. A loss of proteostasis is associated with aging and age-related disorders in diverse model systems, moreover, genetic or pharmacological enhancement of the proteostasis network has been shown to extend lifespan and suppress age-related disease. However, our understanding of the relationship between aging, proteostasis, and the proteostasis network remains unclear. Here, we propose, from studies in Caenorhabditis elegans, that proteostasis collapse is not gradual but rather a sudden and early life event that triggers proteome mismanagement, thereby affecting a multitude of downstream processes. Furthermore, we propose that this phenomenon is not stochastic but is instead a programmed re-modeling of the proteostasis network that may be conserved in other species. As such, we postulate that changes in the proteostasis network may be one of the earliest events dictating healthy aging in metazoans.
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The maintenance of the proteome is essential to preserve cell functionality and the ability to respond and adapt to the changing environment. This is regulated by the proteostasis network, a dedicated set of molecular components comprised of molecular chaperones and protein clearance mechanisms, regulated by cell stress signaling pathways, that prevents the toxicity associated with protein misfolding and accumulation of toxic aggregates in different subcellular compartments and tissues. The efficiency of the proteostasis network declines with age and this failure in protein homeostasis has been proposed to underlie the basis of common age-related human disorders. The current advances in the understanding of the mechanisms and regulation of proteostasis and of the different types of digressions in this process in aging have turned the attention toward the therapeutic opportunities offered by the restoration of proteostasis in age-associated degenerative diseases. Here, we discuss some of the unresolved questions on proteostasis that need to be addressed to enhance healthspan and to diminish the pathology associated with persistent protein damage.
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Haploinsufficiency, a dominant phenotype caused by a heterozygous loss-of-function mutation, has been rarely observed. However, high-dimensional single-cell phenotyping of yeast morphological characteristics revealed haploinsufficiency phenotypes for more than half of 1,112 essential genes under optimal growth conditions. Additionally, 40% of the essential genes with no obvious phenotype under optimal growth conditions displayed haploinsufficiency under severe growth conditions. Haploinsufficiency was detected more frequently in essential genes than in nonessential genes. Similar haploinsufficiency phenotypes were observed mostly in mutants with heterozygous deletion of functionally related genes, suggesting that haploinsufficiency phenotypes were caused by functional defects of the genes. A global view of the gene network was presented based on the similarities of the haploinsufficiency phenotypes. Our dataset contains rich information regarding essential gene functions, providing evidence that single-cell phenotyping is a powerful approach, even in the heterozygous condition, for analyzing complex biological systems.
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Aging is a complex process regulated by multiple cellular pathways, including the proteostasis network. The proteostasis network consists of molecular chaperones, stress-response transcription factors, and protein degradation machines that sense and respond to proteotoxic stress and protein misfolding to ensure cell viability. A loss of proteostasis is associated with aging and age-related disorders in diverse model systems, moreover, genetic or pharmacological enhancement of the proteostasis network has been shown to extend lifespan and suppress age-related disease. However, our understanding of the relationship between aging, proteostasis, and the proteostasis network remains unclear. Here, we propose, from studies in Caenorhabditis elegans, that proteostasis collapse is not gradual but rather a sudden and early life event that triggers proteome mismanagement, thereby affecting a multitude of downstream processes. Furthermore, we propose that this phenomenon is not stochastic but is instead a programmed re-modeling of the proteostasis network that may be conserved in other species. As such, we postulate that changes in the proteostasis network may be one of the earliest events dictating healthy aging in metazoans.
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Abstract Aging is associated with a progressive loss of tissue and metabolic homeostasis. This loss can be delayed by single‐gene perturbations, increasing lifespan. How such perturbations affect metabolic and proteostatic networks to extend lifespan remains unclear. Here, we address this question by comprehensively characterizing age‐related changes in protein turnover rates in the Drosophila brain, as well as changes in the neuronal metabolome, transcriptome, and carbon flux in long‐lived animals with elevated Jun‐N‐terminal Kinase signaling. We find that these animals exhibit a delayed age‐related decline in protein turnover rates, as well as decreased steady‐state neuronal glucose‐6‐phosphate levels and elevated carbon flux into the pentose phosphate pathway due to the induction of glucose‐6‐phosphate dehydrogenase (G6PD). Over‐expressing G6PD in neurons is sufficient to phenocopy these metabolic and proteostatic changes, as well as extend lifespan. Our study identifies a link between metabolic changes and improved proteostasis in neurons that contributes to the lifespan extension in long‐lived mutants.
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The protein homeostasis (proteostasis) network is a nexus of molecular mechanisms that act in concert to maintain the integrity of the proteome and ensure proper cellular and organismal functionality. Early in life the proteostasis network efficiently preserves the functionality of the proteome, however, as the organism ages, or due to mutations or environmental insults, subsets of inherently unstable proteins misfold and form insoluble aggregates that accrue within the cell. These aberrant protein aggregates jeopardize cellular viability and, in some cases, underlie the development of devastating illnesses. Hence, the accumulation of protein aggregates activates different nodes of the proteostasis network that refold aberrantly folded polypeptides, or direct them for degradation. The proteostasis network apparently functions within the cell, however, a myriad of studies indicate that this nexus of mechanisms is regulated at the organismal level by signaling pathways. It was also discovered that the proteostasis network differentially responds to dissimilar proteotoxic insults by tailoring its response according to the specific challenge that cells encounter. In this mini-review, we delineate the proteostasis-regulating neuronal mechanisms, describe the indications that the proteostasis network differentially responds to distinct proteotoxic challenges, and highlight possible future clinical prospects of these insights.
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