-
EMBO Molecular Medicine Sep 2017Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a point mutation in encoding A-type lamins. Progerin, a...
Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a point mutation in encoding A-type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped promyelocytic nuclear bodies, identified as novel biomarkers in late passage HGPS cell lines. We found that the proteasome inhibitor MG132 induces progerin degradation through macroautophagy and strongly reduces progerin production through downregulation of SRSF-1 and SRSF-5 accumulation, controlling prelamin A mRNA aberrant splicing. MG132 treatment improves cellular HGPS phenotypes. MG132 injection in skeletal muscle of mice locally reduces SRSF-1 expression and progerin levels. Altogether, we demonstrate progerin reduction based on MG132 dual action and shed light on a promising class of molecules toward a potential therapy for children with HGPS.
Topics: Animals; Autophagy; Female; Humans; Lamin Type A; Leupeptins; Male; Mice; Mice, Knockout; Progeria; Proteolysis; RNA Splicing; Serine-Arginine Splicing Factors
PubMed: 28674081
DOI: 10.15252/emmm.201607315 -
Indian Pediatrics Nov 1992
Topics: Child; Coronary Disease; Female; Humans; Progeria
PubMed: 1294507
DOI: No ID Found -
Indian Pediatrics Nov 1981
Topics: Child; Developmental Disabilities; Humans; Progeria
PubMed: 6176539
DOI: No ID Found -
Postgraduate Medicine Mar 1973
Topics: Child, Preschool; Humans; Male; Progeria
PubMed: 4691210
DOI: 10.1080/00325481.1973.11713407 -
The Journals of Gerontology. Series A,... Jan 2007Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal genetic disorder that is characterized by segmental accelerated aging. The major causal mutation associated... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal genetic disorder that is characterized by segmental accelerated aging. The major causal mutation associated with HGPS triggers abnormal messenger RNA splicing of the lamin A gene leading to changes in the nuclear architecture. To date, two models have been proposed to explain how mutations in the lamin A gene could lead to HGPS, structural fragility and altered gene expression. We favor a compatible model that links HGPS to stem cell-driven tissue regeneration. In this model, nuclear fragility of lamin A-deficient cells increases apoptotic cell death to levels that exhaust tissues' ability for stem cell-driven regeneration. Tissue-specific differences in cell death or regenerative potential, or both, result in the tissue-specific segmental aging pattern seen in HGPS. We propose that the pattern of aging-related conditions present or absent in HGPS can provide insight into the genetic and environmental factors that contribute to normal aging.
Topics: Aging; Animals; Apoptosis; Disease Progression; Genetic Predisposition to Disease; Humans; Lamin Type A; Mutation; Progeria; RNA, Messenger; Regeneration; Stem Cells
PubMed: 17301031
DOI: 10.1093/gerona/62.1.3 -
Medecine Sciences : M/S Apr 2021Hutchinson-Gilford Progeria (acute premature aging) is caused by a de novo point mutation in the lamin A gene. Recently, this mutation has been accurately corrected by...
Hutchinson-Gilford Progeria (acute premature aging) is caused by a de novo point mutation in the lamin A gene. Recently, this mutation has been accurately corrected by base editing in patient cell lines and in a mouse model, resulting in nearly complete reversal to a normal phenotype. This success opens the perspective for clinical applications in Progeria and other diseases.
Topics: Animals; Disease Models, Animal; Fluorescent Antibody Technique; Gene Editing; Humans; Lamin Type A; Mice; Point Mutation; Progeria; Targeted Gene Repair
PubMed: 33908864
DOI: 10.1051/medsci/2021054 -
The Journal of Pediatrics Apr 1972
Review
Topics: Abortion, Spontaneous; Adolescent; Adult; Age Factors; Alopecia; Birth Weight; Bone and Bones; Child; Child, Preschool; Consanguinity; Dentition; Facial Expression; Female; Genitalia; Geography; Gestational Age; Growth Disorders; History, 19th Century; History, 20th Century; Humans; Hydrocephalus, Normal Pressure; Infant; Infant, Newborn; Intelligence; Male; Middle Aged; Nails, Malformed; Parents; Pedigree; Personality; Pregnancy; Progeria; Racial Groups; Radiography; Sex Factors
PubMed: 4552697
DOI: 10.1016/s0022-3476(72)80229-4 -
Cellular and Molecular Life Sciences :... Feb 2023Barrier-to-autointegration factor (BAF/BANF) is a nuclear lamina protein essential for nuclear integrity, chromatin structure, and genome stability. Whereas complete...
Barrier-to-autointegration factor (BAF/BANF) is a nuclear lamina protein essential for nuclear integrity, chromatin structure, and genome stability. Whereas complete loss of BAF causes lethality in multiple organisms, the A12T missense mutation of the BANF1 gene in humans causes a premature aging syndrome, called NĂ©stor-Guillermo Progeria Syndrome (NGPS). Here, we report the first in vivo animal investigation of progeroid BAF, using CRISPR editing to introduce the NGPS mutation into the endogenous Drosophila baf gene. Progeroid BAF adults are born at expected frequencies, demonstrating that this BAF variant retains some function. However, tissue homeostasis is affected, supported by studies of the ovary, a tissue that depends upon BAF for stem cell survival and continuous oocyte production. We find that progeroid BAF causes defects in germline stem cell mitosis that delay anaphase progression and compromise chromosome segregation. We link these defects to decreased recruitment of centromeric proteins of the kinetochore, indicating dysfunction of cenBAF, a localized pool of dephosphorylated BAF produced by Protein Phosphatase PP4. We show that DNA damage increases in progenitor germ cells, which causes germ cell death due to activation of the DNA damage transducer kinase Chk2. Mitotic defects appear widespread, as aberrant chromosome segregation and increased apoptosis occur in another tissue. Together, these data highlight the importance of BAF in establishing centromeric structures critical for mitosis. Further, these studies link defects in cenBAF function to activation of a checkpoint that depletes progenitor reserves critical for tissue homeostasis, aligning with phenotypes of NGPS patients.
Topics: Animals; Female; Humans; Drosophila; Progeria; DNA-Binding Proteins; Nuclear Proteins; Centromere; Homeostasis
PubMed: 36842139
DOI: 10.1007/s00018-023-04721-y -
Clinical Neurophysiology : Official... Aug 2020
Topics: Adult; Eye Movements; Humans; Male; Progeria; Saccades
PubMed: 32563167
DOI: 10.1016/j.clinph.2020.05.019 -
Ryoikibetsu Shokogun Shirizu 2000
Review
Topics: DNA; Diagnosis, Differential; Forkhead Box Protein M1; Forkhead Transcription Factors; Humans; Progeria; Prognosis; Transcription Factors; Transforming Growth Factor beta
PubMed: 11212729
DOI: No ID Found