Towards delineating the chain of events that cause premature senescence in the accelerated aging syndrome Hutchinson–Gilford progeria (HGPS)

Abstract

The metazoan nucleus is equipped with a meshwork of intermediate filament proteins called the A- and B-type lamins. Lamins lie beneath the inner nuclear membrane and serve as a nexus to maintain the architectural integrity of the nucleus, chromatin organization, DNA repair and replication and to regulate nucleocytoplasmic transport. Perturbations or mutations in various components of the nuclear lamina result in a large spectrum of human diseases collectively called laminopathies. One of the most well-characterized laminopathies is Hutchinson–Gilford progeria (HGPS), a rare segmental premature aging syndrome that resembles many features of normal human aging. HGPS patients exhibit alopecia, skin abnormalities, osteoporosis and succumb to cardiovascular complications in their teens. HGPS is caused by a mutation in LMNA, resulting in a mutated form of lamin A, termed progerin. Progerin expression results in a myriad of cellular phenotypes including abnormal nuclear morphology, loss of peripheral heterochromatin, transcriptional changes, DNA replication defects, DNA damage and premature cellular senescence. A key challenge is to elucidate how these different phenotypes are causally and mechanistically linked. In this mini-review, we highlight some key findings and present a model on how progerin-induced phenotypes may be temporally and mechanistically linked.

Síndrome Progeroide de Hutchinson-Gilford: Uma revisão integrativa / Hutchinson-Gilford Progeroid Syndrome: An Integrative Review

“…2021 modificações das histonas, sendo que elas também se apresentam nas células de indivíduos idosos, o que indica uma possível influência no envelhecimento normal. 2,6,9 Por fim, as células que expressam progerina apresentam agregados de telômeros, várias aberrações cromossômicas e, até mesmo, aneuploidias. 10 Devido a extensa perda conformacional da cromatina, a instabilidade genômica e as diversas anormalidades do envelope nuclear, as células são conduzidas a um estado de senescência pela ativação de uma via supressora tumoral mediada pela proteína p53.…”

“…1 Essa doença do envelhecimento precoce é extremamente rara, apresenta incidência de 1 para cada 4 a 8 milhões de nascidos vivos e é terminantemente fatal devido a complicações cardiovasculares ateroscleróticas, com uma expectativa de vida média de 13 anos. [2][3][4][5] Os pacientes portadores dessa síndrome apresentam um fenótipo praticamente constante com intensa semelhança um com o outro, porém seu diagnóstico é frequentemente errôneo haja vista sua baixa taxa de incidência. 1 O quadro clínico apresentado pelos pacientes é marcado por características próprias do envelhecimento prematuro, incluindo perda extensa do panículo adiposo, pigmentação aberrante, alopecia, fácies característica, rigidez das articulações, alterações ósseas e aderência anormal da pele sobre o abdome e coxas.…”

MG132 Induces Progerin Clearance and Improves Disease Phenotypes in HGPS-like Patients’ Cells

“…Among the deregulated signaling pathways, an enhanced NF-κB activity is responsible for the inflammatory signaling and the senescence-associated secretory phenotype [ 37 ]. Farnesylated progerin has also been shown to impair nuclear mechanical characteristics, DNA damage responses, chromatin organization, telomere length, gene expression, mitosis, stem cell exhaustion, and the deregulation of extracellular matrix production and remodeling [ 21 , 38 , 39 ].…”

Lamin A to Z in normal aging

“…Stepping back, there are also numerous studies linking progerin, and to a lesser extent prelamin A, expression to loss of heterochromatin. Links to progerin are thoroughly described in a recent review [108].…”