Genetics of aging, progeria and lamin disorders

Ghosh, Shreya; Zhou, Zhongjun

doi:10.1016/j.gde.2014.05.003

Cited by 59 publications

(40 citation statements)

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“…In this study, we analyzed the kinetics and consequences of the previously reported decrease in LAP2α levels in HGPS cells Misteli 2005, 2008;Cenni et al 2011;Zhang et al 2011) and investigated whether LAP2α down-regulation may be causally involved in proliferation defects of HGPS cells (Burtner and Kennedy 2010;Ghosh and Zhou 2014;Gordon et al 2014). In all HGPS cell cultures analyzed, LAP2α showed a highly heterogeneous distribution of expression, ranging from cells with high/normal LAP2α levels to cells with low or undetectable LAP2α expression, which was inversely correlated with progerin expression levels.…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence, progerin cannot undergo the final proteolytic processing step and retains the C-terminal farnesyl group, leading to its stable association with the INM ). Progerin acts in a dominant-negative fashion and induces various cellular defects-including alterations in nuclear shape and structure, mechanotransduction, gene expression, various signaling pathways, DNA repair, and chromatin organization-and subsequently leads to premature senescence (Ghosh and Zhou 2014;Gordon et al 2014).…”

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confidence: 99%

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Proliferation of progeria cells is enhanced by lamina-associated polypeptide 2α (LAP2α) through expression of extracellular matrix proteins

et al. 2015

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Lamina-associated polypeptide 2α (LAP2α) localizes throughout the nucleoplasm and interacts with the fraction of lamins A/C that is not associated with the peripheral nuclear lamina. The LAP2α–lamin A/C complex negatively affects cell proliferation. Lamins A/C are encoded by LMNA, a single heterozygous mutation of which causes Hutchinson-Gilford progeria syndrome (HGPS). This mutation generates the lamin A variant progerin, which we show here leads to loss of LAP2α and nucleoplasmic lamins A/C, impaired proliferation, and down-regulation of extracellular matrix components. Surprisingly, contrary to wild-type cells, ectopic expression of LAP2α in cells expressing progerin restores proliferation and extracellular matrix expression but not the levels of nucleoplasmic lamins A/C. We conclude that, in addition to its cell cycle-inhibiting function with lamins A/C, LAP2α can also regulate extracellular matrix components independently of lamins A/C, which may help explain the proliferation-promoting function of LAP2α in cells expressing progerin.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Proliferation of progeria cells is enhanced by lamina-associated polypeptide 2α (LAP2α) through expression of extracellular matrix proteins

et al. 2015

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“…Mutations in lamin A cause lipodystrophies, a class of disorders characterized by a selective loss of adipose tissue. 5 While the mechanisms in Lamin A associated lipodystrophies are unclear, previous studies have suggested that mutant lamin A sequesters the critical lipogenic transcription factor Sterol regulatory Binding Protein 1 (SREBP 1) at the nuclear periphery thereby reducing availability of the protein for transcriptional activation. 28 Rolyan et al, (2015) also demonstrated a reduced expression of the SREBP1 and 2 genes in tissues from the Lamin B1 overexpressing mice.…”

Section: Epigenetic and Transcriptional Pathways Link Lipid Synthesismentioning

confidence: 99%

“…3,4 In addition, the nuclear lamina has been shown to play an important role in both normal and pathological aging. 5,6 Autosomal Dominant Leukodystrophy is caused by mutations involving the Lamin B1 gene While at least 12 distinct disorders have been associated with mutations in the LMNA gene, only one disease, Autosomal Dominant Leukodystrophy (ADLD), has so far been linked to mutations involving lamin B1. 7,8 The majority of ADLD cases are caused by duplications involving the lamin B1 gene locus that results in increased lamin B1 protein expression.…”

Section: Introductionmentioning

confidence: 99%

Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies

Padiath

2016

Nucleus

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Autosomal Dominant Leukodystrophy (ADLD), a fatal adult onset demyelinating disorder, is the only human disease that has been linked to mutations of the nuclear lamina protein, lamin B1, and is primarily caused by duplications of the LMNB1 gene. Why CNS myelin is specifically targeted and the mechanisms underlying ADLD are unclear. Recent work from our group has demonstrated that over expression of lamin B1 in oligodendrocytes, the myelin producing cells in the CNS, resulted in age dependent epigenetic modifications, transcriptional down-regulation of lipogenic gene expression and significant reductions of myelin-enriched lipids. Given the high lipid content of meylin, we hypothesize that lipid loss is one of the primary drivers of the demyelination phenotype. These results can, at least partially, explain the age dependence and cell type specificity in ADLD and are discussed in the context of the existing literature, in an attempt to delineate potential pathways underlying the disease phenotype.

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“…Premature aging disorders (progeroid syndromes) as Werner syndrome and progeria syndrome Hutchinson-Gilford have been subject of immense interest and that recapitulate many of the phenotypes observed in physiological aging. They not only serve as models for studying the processes of normal aging but also provide valuable insight into the intricate mechanism of senescence [32].…”

Section: Genetic Mechanismsmentioning

confidence: 99%

Theories of Human Aging of Molecules to Society

Cabrera¹

2015

MOJI

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Aging is a process of deterioration of physiological functions, time-dependent, leading to homeoestenosis. The causes and mechanisms of this process are not yet fully clarified so have issued numerous theories to explain it.The article reviews the major theories of human aging, while proposing a classification that covers the fundamental mechanisms, including deregulation of the immune response (oxy-inflamm-aging) as one of the most cited today.The theories also include those relating to the psychosocial aspects of aging, taking a holistic approach to this biological process of humans.

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Genetics of aging, progeria and lamin disorders

Cited by 59 publications

References 57 publications

Proliferation of progeria cells is enhanced by lamina-associated polypeptide 2α (LAP2α) through expression of extracellular matrix proteins

Proliferation of progeria cells is enhanced by lamina-associated polypeptide 2α (LAP2α) through expression of extracellular matrix proteins

Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies

Theories of Human Aging of Molecules to Society

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