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Skin Disease in Laminopathy-Associated Premature Aging

      The nuclear lamina, a protein network located under the nuclear membrane, has during the past decade found increasing interest due to its significant involvement in a range of genetic diseases, including the segmental premature aging syndromes Hutchinson–Gilford progeria syndrome, restrictive dermopathy, and atypical Werner syndrome. In this review we examine these diseases, some caused by mutations in the LMNA gene, and their skin disease features. Advances within this area might also provide novel insights into the biology of skin aging, as recent data suggest that low levels of progerin are expressed in unaffected individuals and these levels increase with aging.
      HGPS
      Hutchinson–Gilford progeria syndrome
      LBR
      lamin B receptor
      OMIM
      Online Inheritance in Man
      RD
      restrictive dermopathy
      SASP
      senescence-associated secretory phenotype

      Introduction

      Laminopathies are diseases caused by a heterogeneous family of mutations either directly affecting the LMNA gene (causing primary laminopathies
      • Hegele R.
      LMNA mutation position predicts organ system involvement in laminopathies.
      )) or affecting genes coding for B-type lamins, prelamin A processing proteins, or lamin-binding proteins (causing secondary laminopathies (
      • Broers J.L.V.
      • Ramaekers F.C.S.
      • Bonne G.
      • et al.
      Nuclear lamins: laminopathies and their role in premature ageing.
      ;
      • Landires I.
      • Pascale J.M.
      • Motta J.
      The position of the mutation within the LMNA gene determines the type and extent of tissue involvement in laminopathies.
      )). Four of these laminopathies are classified as premature-aging syndromes: Hutchinson–Gilford progeria syndrome (HGPS, Online Inheritance in Man (OMIM) #176670), atypical progeroid syndrome, restrictive dermopathy (RD, OMIM #275210), and atypical Werner syndrome (OMIM #277700).
      HGPS is a rare and fatal genetic disorder with a stark phenotype of premature senility. Although first described in 1886 by Hutchinson and in 1904 by Gilford (
      • Hutchinson J.
      Congenital absence of hair and mammary glands with atrophic condition of the skin and its appendages, in a boy whose mother had been almost wholly bald from alopecia areata from the age of six.
      ;
      • Gilford H.
      On a condition of mixed premature and immature development.
      ), the genetic cause of progeria was found only in 2003 (
      • de Sandre-Giovannoli A.
      • Bernard R.
      • Cau P.
      • et al.
      Lamin a truncation in Hutchinson-Gilford progeria.
      ;
      • Eriksson M.
      • Brown W.T.
      • Gordon L.B.
      • et al.
      Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome.
      ). Numerous other mutations have since been found to cause HGPS (Figure 1a) (
      • Fukuchi K.
      • Katsuya T.
      • Sugimoto K.
      • et al.
      LMNA mutation in a 45 year old Japanese subject with Hutchinson-Gilford progeria syndrome.
      ;
      • Dechat T.
      • Shimi T.
      • Adam S.
      Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging.
      ;
      • Moulson C.
      • Fong L.
      • Gardner J.
      Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes.
      ;
      • Hisama F.M.
      • Lessel D.
      • Leistritz D.
      • et al.
      Coronary artery disease in a Werner syndrome-like form of progeria characterized by low levels of progerin, a splice variant of lamin A.
      ;
      • Reunert J.
      • Wentzell R.
      • Walter M.
      • et al.
      Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn.
      ); however, the vast majority of HGPS cases (>90%) are caused by the de novo c.1824C>T, p.G608G mutation in the lamin A gene (Figure 1a) that results in the increased activation of a cryptic splice site in exon 11 of LMNA. This increases the production and accumulation of a partially processed prelamin A protein, called progerin (Figure 1b) (
      • Eriksson M.
      • Brown W.T.
      • Gordon L.B.
      • et al.
      Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome.
      ;
      • Goldman A.
      • Erdos M.
      • Eriksson M.
      • et al.
      Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome.
      ).
      Figure thumbnail gr1
      Figure 1Impaired lamin A/C in segmental progeroid syndromes. (a) A list of selected LMNA mutations causing atypical Werner syndrome (AWS), Hutchinson–Gilford progeria syndrome (HGPS), and atypical progeroid syndrome (APS). Exons 1–9 and a section of 10 encode lamin C (lamin C–specific amino acids in green). Lamin A results from alternative splicing using exons 1–12, without the lamin C–specific part of exon 10. Conserved α-helical regions of the central rod domain are labeled coil 1/1B/2A+2B. Underlying numbers refer to primary sequence locations. NLS, nuclear localization signal. (b) Prelamin A maturation in wild type, HGPS (and several APS), and restrictive dermopathy (RD). (c) Skin fibroblast nuclei, blue (DNA), young/unaffected, aged/unaffected, and HGPS, far right shows the HGPS nuclei in red (progerin).
      Patients with HGPS are born without noticeable symptoms; however, they fail to thrive, and from ∼6 to 18 months of age display sclerodermatous skin with patches that are hyper- or hypopigmented, as well as a loss of subcutaneous fat. As the first signs of HGPS appear in the skin, and as the skin undergoes the most marked change in patients, several groups have performed research specifically on the effects of progerin in the skin. Skin-specific symptoms include alopecia, dyspigmentation, and prominent veins followed by the occurrence of a thin epidermis, dermal fibrosis, and a loss of skin appendages (hair follicles, sweat glands, and sebaceous glands), as well as the development of tight skin over the abdomen and thighs by the third year of life. Other early symptoms include short stature and low body weight. Patients have a horse-riding stance, short clavicles, osteolysis, and joint stiffness. These symptoms result in an aged appearance. Death occurs by the early teenage years, often caused by cardiovascular complications due to atherosclerosis (
      • Gillar P.J.
      • Kaye C.I.
      • McCourt J.W.
      Progressive early dermatologic changes in Hutchinson-Gilford progeria syndrome.
      ;
      • Rodríguez J.I.
      • Pérez-Alonso P.
      • Funes R.
      • et al.
      Lethal neonatal Hutchinson-Gilford progeria syndrome.
      ;
      • Eriksson M.
      • Brown W.T.
      • Gordon L.B.
      • et al.
      Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome.
      ;
      • Merideth M.A.
      • Gordon L.B.
      • Clauss S.
      • et al.
      Phenotype and course of Hutchinson–Gilford progeria syndrome.
      ;
      • Salamat M.
      • Dhar P.K.
      • Neagu D.L.
      • et al.
      Aortic calcification in a patient with Hutchinson-Gilford progeria syndrome.
      ).
      RD is a rare and lethal autosomal recessive disease, caused by loss-of-function mutations in ZMPSTE24 (also referred to as FACE1, OMIM #606480) (
      • Navarro C.L.
      • Esteves-Vieira V.
      • Courrier S.
      • et al.
      New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update.
      ). The protein product of ZMPSTE24 is a zinc metalloproteinase that is involved in the processing of lamin A (Figure 1b). Skin histology revealed thin epidermal layers with regular structure and a flat epidermal–dermal junction. Sebaceous glands and hair follicles were immature and poorly developed, and the dermis showed parallel collagen bundles and an almost total lack of elastic fibers (
      • Khanna P.
      • Opitz J.M.
      • Gilbert-Barness E.
      Restrictive dermopathy: report and review.
      ;
      • Smigiel R.
      • Jakubiak A.
      • Esteves-Vieira V.
      • et al.
      Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with restrictive dermopathy and review of the mutations described in the literature.
      ).
      Children with RD show intrauterine growth retardation, as well as a decreased fetal movement. After birth, they display a characteristic thin, translucent, tight skin, lacking eyebrows and eyelashes, joint contractures, respiratory insufficiency, a small pinched nose, micrognathia, and mouth in a fixed “o” shape. Respiratory failure caused by the tight skin most often leads to neonatal death within several weeks of birth (
      • Mok Q.
      • Curley R.
      • Tolmie J.L.
      • et al.
      Restrictive dermopathy: a report of three cases.
      ;
      • Smigiel R.
      • Jakubiak A.
      • Esteves-Vieira V.
      • et al.
      Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with restrictive dermopathy and review of the mutations described in the literature.
      ).
      Atypical Werner syndrome was described first by Otto Werner in 1904. Unlike Werner syndrome, which is caused by mutations in WRN (
      • Yu C.E.
      • Oshima J.
      • Fu Y.H.
      • et al.
      Positional cloning of the Werner's syndrome gene.
      ), atypical Werner syndrome is caused by mutations in other genes, with a minority of these cases found to be caused by heterozygous mutations in LMNA (
      • Chen L.
      • Lee L.
      • Kudlow B.A.
      • et al.
      LMNA mutations in atypical Werner's syndrome.
      ). Werner syndrome is called the “progeria of the adult,” with symptoms emerging in the teenage years. The initial pubertal growth failure is later followed by skin atrophy, ulcers, cataracts, atherosclerosis, hair graying and alopecia, type 2 diabetes mellitus, and osteoporosis. Malignancies, reduced fertility, and gonadal atrophy can also occur, with cardiovascular disease and cancer being the most common causes of death, occurring at a mean age of 54 years (
      • Hisama F.M.
      • Lessel D.
      • Leistritz D.
      • et al.
      Coronary artery disease in a Werner syndrome-like form of progeria characterized by low levels of progerin, a splice variant of lamin A.
      ,
      • Hisama F.M.
      • Kubisch C.
      • Martin G.M.
      • et al.
      Clinical utility gene card for: Werner syndrome.
      ).
      Progeroid diseases caused by LMNA mutations that are not associated with characterized diseases are classified as atypical progeroid syndromes. By definition, these diseases have a varied disease pathology, running the gamut from RD-like neonatally lethal tight-skin syndromes (
      • Navarro C.
      • Sandre-Giovannoli D.
      • Bernard R.
      Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy.
      ) to HGPS-like disorders with symptoms of growth retardation, partially alopecia, skin atrophy, and diabetes (
      • Garg A.
      • Subramanyam L.
      • Agarwal A.K.
      • et al.
      Atypical progeroid syndrome due to heterozygous missense LMNA mutations.
      ). In the more severe atypical progeroid syndrome and with early onset, progerin accumulation occurs at a greater level than in HGPS, thought to be a factor in the increased severity of the disease (
      • Moulson C.
      • Fong L.
      • Gardner J.
      Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes.
      ).

      The Molecular Genetics of HGPS and RD

      To date, 464 different mutations from 2,251 individuals have been identified in LMNA (
      • The UMD-LMNA mutations database
      ). LMNA (OMIM #150330) consists of exons 1–12 and encodes prelamin A that is converted to lamin A (Figure 1b). Lamin A is localized to the inner nuclear membrane, where it gives shape, strength, and support to the nucleus and regulates gene expression by binding DNA as well as sequestering heterochromatin to the nuclear periphery. It has also been associated with DNA replication and repair and organization of nuclear pore complexes and chromatin (
      • Broers J.L.V.
      • Ramaekers F.C.S.
      • Bonne G.
      • et al.
      Nuclear lamins: laminopathies and their role in premature ageing.
      ;
      • Dechat T.
      • Pfleghaar K.
      • Sengupta K.
      • et al.
      Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin.
      ;
      • Dittmer T.A.
      • Sahni N.
      • Kubben N.
      • et al.
      Systematic identification of pathological lamin A interactors.
      ).
      The LMNA gene also produces lamin C and the minor AΔ10 and C2 proteins by alternative splicing within exon 10 (
      • Lin F.
      • Worman H.J.
      Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C.
      ). The N-terminal head domain is encoded by exon 1, exons 1–6 code the central rod domain, and the C-terminal tail domain is encoded by exons 7–9. Exon 7 also encodes a 6-amino-acid nuclear localization signal allowing the protein to be imported into the nucleus (Figure 1a) (
      • Fisher D.
      • Chaudhary N.
      cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins.
      ;
      • Lin F.
      • Worman H.J.
      Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C.
      ;
      • Rout M.P.
      The nuclear pore complex as a transport machine.
      ). Exons 11 and 12 are specific to lamin A.
      A-type lamins are only expressed in differentiated cells, suggesting that they are instrumental in stabilizing differential gene expression (
      • Stick R.
      • Hausen P.
      Changes in the nuclear lamina composition during early development of Xenopus laevis.
      ;
      • Lehner C.F.
      • Stick R.
      • Eppenberger H.M.
      • et al.
      Differential expression of nuclear lamin proteins during chicken development.
      ;
      • Röber R.A.
      • Weber K.
      • Osborn M.
      Differential timing of nuclear lamin A/C expression in the various organs of the mouse embryo and the young animal: a developmental study.
      ;
      • Zorenc A.H.G.
      An alternative splicing product of the lamin A/C gene lacks exon 10.
      ). Lamins A and C are identical for the initial 566 amino acids. Lamin C terminates with 6 unique amino acids, whereas lamin A has 98 unique amino acids, ending in a CaaX motif on exon 12. This motif is key for posttranslational processing. It is modified, aiding prelamin A integration into the nuclear lamina, and subsequently removed during the maturation of lamin A (
      • Pendás A.M.
      • Zhou Z.
      • Cadiñanos J.
      • et al.
      Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice.
      ;
      • Barrowman J.
      • Hamblet C.
      • George C.M.
      • et al.
      Analysis of prelamin A biogenesis reveals the nucleus to be a CaaX processing compartment.
      ) that takes place in the nucleus (
      • Lutz R.J.
      • Trujillo M.A.
      • Denham K.S.
      • et al.
      Nucleoplasmic localization of prelamin A: implications for prenylation-dependent lamin A assembly into the nuclear lamina.
      ).
      Posttranslational modification of prelamin A (Figure 1b):
      • (1)
        An initial prenylation step attaches a farnesyl or geranylgeranyl isoprenoid group to the cysteine of the CaaX motif that lies at the C-terminal end of prelamin A.
      • (2)
        The -aaX amino acids of this motif are then removed by the RCE1 or the FACE1 enzymes.
      • (3)
        The exposed C-terminal farnesylcysteine is then methylated by a carboxymethyltransferase, isoprenylcysteine carboxyl methyltransferase (
        • Holtz D.
        • Tanaka R.A.
        • Hartwig J.
        • et al.
        The CaaX motif of lamin A functions in conjunction with the nuclear localization signal to target assembly to the nuclear envelope.
        ).
      • (4)
        At the nuclear membrane, a final cleavage step occurs as FACE1 removes the carboxy-terminal 15 amino acids and the farnesylcysteine methyl ester group from prelamin A, resulting in mature Lamin A (
        • Vergnes L.
        • Peterfy M.
        • Bergo M.O.
        • et al.
        Lamin B1 is required for mouse development and nuclear integrity.
        ).
      The mutated prelamin A produced in HGPS patients can undergo the initial three steps of posttranslational maturation. However, the G608G mutation (or the less common G608S, V607V, or IVS11+1G>A; Figure 1a) results in the deletion of 150 nucleotides containing the second cleavage site recognized by ZMPSTE24, and hence the fourth step cannot be completed, resulting in a permanently farnesylated protein (Figure 1b). This improperly processed protein, progerin, is thought to cause the disease phenotype (
      • Capell B.
      • Erdos M.
      • Madigan J.
      • et al.
      Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome.
      ;
      • Young S.G.
      • Fong L.G.
      • Michaelis S.
      Prelamin A, Zmpste24, misshapen cell nuclei, and progeria—new evidence suggesting that protein farnesylation could be important for disease pathogenesis.
      ). In RD patient cells, the lack of a functional ZMPSTE24 enzyme means that the final cleavage step cannot be performed and leads to the accumulation of a farnesylated prelamin A (Figure 1b) (
      • Smigiel R.
      • Jakubiak A.
      • Esteves-Vieira V.
      • et al.
      Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with restrictive dermopathy and review of the mutations described in the literature.
      ).
      Progerin remains erroneously farnesylated, causing it to localize to the nuclear membrane, resulting in a disruption to the nuclear laminar integrity and defects in nuclear structure and function. HGPS patient fibroblasts are characterized by dysmorphic nuclei with altered size and shape, a thickened nuclear lamina, a loss of peripheral heterochromatin, the clustering of nuclear pores, as well as the presence of lobules, wrinkles, and herniations of the nuclear envelope (Figure 1c) (
      • Eriksson M.
      • Brown W.T.
      • Gordon L.B.
      • et al.
      Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome.
      ;
      • Goldman A.
      • Erdos M.
      • Eriksson M.
      • et al.
      Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome.
      ;
      • Scaffidi P.
      • Misteli T.
      Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome.
      ). These defects worsen as the cell cultures are passaged and are correlated with the intranuclear accumulation of progerin (
      • Goldman A.
      • Erdos M.
      • Eriksson M.
      • et al.
      Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome.
      ). A recent study of Werner syndrome on human embryonic stem cells showed changes in heterochromatin architecture that was also found in mesenchymal stem cells from aged individuals, adding to the evidence of heterochromatin disorganization as a factor in normal aging (
      • Zhang W.
      • Li J.
      • Suzuki K.
      • et al.
      A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.
      ).

      Evidence for Lamin Involvement in Normal Aging

      Progerin has been found not only in HGPS patients but also in healthy aged individuals and normal cell lines (
      • Scaffidi P.
      • Misteli T.
      Lamin A-dependent nuclear defects in human aging.
      ;
      • Cao K.
      • Capell B.C.
      • Erdos M.R.
      • et al.
      A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells.
      ;
      • McClintock D.
      • Ratner D.
      • Lokuge M.
      • et al.
      The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin.
      ;
      • Rodriguez S.
      • Coppedè F.
      • Sagelius H.
      • et al.
      Increased expression of the Hutchinson–Gilford progeria syndrome truncated lamin A transcript during cell aging.
      ). An increasing level of progerin in passaged HGPS cells has also been shown to correlate to the more severe defects seen in late-passage cells (
      • Goldman A.
      • Erdos M.
      • Eriksson M.
      • et al.
      Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome.
      ;
      • Moulson C.
      • Fong L.
      • Gardner J.
      Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes.
      ) (Figure 2a). Naturally, the question arises of whether pathological aging is rooted in the accumulation of progerin over a lifetime of aging. Research in this area has shown that progerin mRNA levels are consistent between groups of young and aged individuals (
      • Scaffidi P.
      • Misteli T.
      Lamin A-dependent nuclear defects in human aging.
      ). Skin fibroblasts from healthy individuals grown in culture, however, do show an increase in progerin mRNA transcript levels with increased time in culture (
      • Rodriguez S.
      • Coppedè F.
      • Sagelius H.
      • et al.
      Increased expression of the Hutchinson–Gilford progeria syndrome truncated lamin A transcript during cell aging.
      ). Studies on fibroblasts from healthy adults showed that a small number of cell nuclei stained positively for progerin and that this number increased with the number of passages (
      • Cao K.
      • Capell B.C.
      • Erdos M.R.
      • et al.
      A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells.
      ).
      Figure thumbnail gr2
      Figure 2Histopathology of progerin expression. (a) Disease severity increases with higher levels of progerin. (b–d and f–h) K5 (green), DNA (blue). (b and f) Mouse lamin (La) A/C (red) is expressed by E17.5. (c and g) Epidermal progerin expression (red), wild-type (c) and progeroid (g) E17.5. Progerin expression follows K5 expression (g). (d and h) Adult wild-type (d), progeroid (h) mouse skin, progerin (red) showing epidermal hyperplasia and hyperparakeratosis (h). (e and i) Hematoxylin and eosin (H&E) staining of wild-type (e) and progeroid (i) mouse skin. (j and k) Impaired wound healing. A 3 mm wound site from wild-type (j) and progeroid (k) mice 7 days after wounding. K5 (blue), dividing cells (red). Disorganized wound edges, delayed reepithelialization, and (inset) increased cell proliferation at wound edges in k. Dashed lines indicate wound centers. Scale bars (bi)=20 μm, (j and k)=200 μm.
      The in vivo studies have also shown the presence of progerin in skin biopsies from unaffected individuals, with progerin-positive nuclei found in dermal fibroblasts and terminally differentiated keratinocytes. In young adult skin samples, progerin-positive fibroblasts were localized near the basement membrane and in the upper layers of the dermis; however, in elderly skin, their numbers increase, and they are also localized in the deep reticular dermis (
      • McClintock D.
      • Ratner D.
      • Lokuge M.
      • et al.
      The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin.
      ). An examination of cardiovascular tissues from HGPS and non-HGPS aged tissues showed the presence of progerin in both (
      • Olive M.
      • Harten I.
      • Mitchell R.
      • et al.
      Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging.
      ).

      Adult Stem Cells in HGPS

      One model for the accelerated aging phenotype seen in HGPS patients, and also possibly a model for physiological aging, is that adult stem cell dysfunction leads to a progressive deterioration of tissue functions. One of the earliest effect of progerin expression is the activation of several Notch cell–signaling pathway components, interfering with the normal function of human mesenchymal stem cells (
      • Scaffidi P.
      • Misteli T.
      Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing.
      ). The Notch cell–signaling pathway is an evolutionarily conserved major regulator of stem-cell differentiation and cell fate that is key to maintaining adult tissue homeostasis (
      • Okuyama R.
      • Tagami H.
      • Aiba S.
      Notch signaling: its role in epidermal homeostasis and in the pathogenesis of skin diseases.
      ). The induced epidermal expression of the human p.G608G mutation in mice was shown to decrease adult stem cell populations in the skin, causing impaired wound healing. Biopsy wounds (3 mm) were examined 4 and 7 days after wounding and were found to have uneven and disorganized wound edges and disrupted reepithelialization in progeroid mice compared with wild-type mice (Figure 2k). The impaired keratinocyte migration may have been caused by the reduced expression of b1- and a6-integrins in cells from progeriod mice compared with wild-type mice. Primary keratinocytes from these animals showed a diminished proliferative potential and ability to form colonies. The epidermal stem cell maintenance protein p63 was also found to be downregulated, and an accompanying activation of DNA repair and premature senescence was implicated as the cause of this loss of adult stem cells (
      • Rosengardten Y.
      • McKenna T.
      • Grochová D.
      • et al.
      Stem cell depletion in Hutchinson-Gilford progeria syndrome.
      ). The in vitro experiments have also supported these findings, showing that progerin causes significant disruption to functions critical to a healthy stem cell population, such as self-renewal, proliferation, migration, and membrane flexibility (
      • Pacheco L.M.
      • Gomez L.A.
      • Dias J.
      • et al.
      Progerin expression disrupts critical adult stem cell functions involved in tissue repair.
      ).

      Inflammation and Senescence in HGPS

      Targeted expression of progerin in the skin resulted in dermal fibrosis and a marked inflammatory cell invasion, as well as a strong upregulation of multiple genes in major inflammatory pathways (
      • Sagelius H.
      • Rosengardten Y.
      • Hanif M.
      • et al.
      Targeted transgenic expression of the mutation causing Hutchinson-Gilford progeria syndrome leads to proliferative and degenerative epidermal disease.
      ;
      • Rosengardten Y.
      • McKenna T.
      • Grochová D.
      • et al.
      Stem cell depletion in Hutchinson-Gilford progeria syndrome.
      ). Exon array studies have also shown inflammatory responses in both HGPS and senescent fibroblasts (
      • Csoka A.
      • English S.
      • Simkevich C.
      • et al.
      Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/ mesenchymal defects in accelerated atherosclerosis.
      ). The cardiovascular tissues of HGPS patients showed regions exhibiting strong inflammation, as well as macrophage infiltration (
      • Olive M.
      • Harten I.
      • Mitchell R.
      • et al.
      Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging.
      ).
      The NF-κB pathway has been shown to be constitutively hyperactivated in transgenic mice carrying the LmnaG609G mutation (
      • Osorio F.G.
      • Barcena C.
      • Soria-Valles C.
      • et al.
      Nuclear lamina defects cause ATM-dependent NF- B activation and link accelerated aging to a systemic inflammatory response.
      ). The ectopic expression of LMNA c.1824C>T in mouse skin during embryogenesis and early development state also resulted in an activated NF-κB and the upregulation of multiple inflammatory response genes (
      • McKenna T.
      • Rosengardten Y.
      • Viceconte N.
      • et al.
      Embryonic expression of the common progeroid lamin A splice mutation arrests postnatal skin development.
      ). Inflammation and senescence have been related as it has been demonstrated that senescent cells secrete inflammatory factors known as “senescence-associated secretory phenotype” or SASP (
      • Coppé J.P.
      • Patil C.K.
      • Rodier F.
      • et al.
      Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
      ). These SASP factors are upregulated in the LMNAG608G progeroid mouse model (
      • Rosengardten Y.
      • McKenna T.
      • Grochová D.
      • et al.
      Stem cell depletion in Hutchinson-Gilford progeria syndrome.
      ) that also showed increased senescence-associated β-galactosidase staining in the interfollicular epidermis. p63, a member of the p53 family that is necessary for the normal development and differentiation of the skin, was downregulated in this same model, suggesting a link between p63 expression, NF- κB signaling, and SASP (
      • Rosengardten Y.
      • McKenna T.
      • Grochová D.
      • et al.
      Stem cell depletion in Hutchinson-Gilford progeria syndrome.
      ).
      Lamin B1 reduction has been associated with keratinocyte senescence, and decreased level of LMNB1 has been shown as a characteristic of HGPS fibroblasts (
      • Dreesen O.
      • Chojnowski A.
      • Ong P.F.
      • et al.
      Lamin B1 fluctuations have differential effects on cellular proliferation and senescence.
      ). The expression of HGPS mutation in mice showed an increase in the ratio of basal to suprabasal expression in the very early stages of the disease development (
      • McKenna T.
      • Rosengardten Y.
      • Viceconte N.
      • et al.
      Embryonic expression of the common progeroid lamin A splice mutation arrests postnatal skin development.
      ). Other characteristics of HGPS senescent cells are a high rate of apoptosis (
      • Bridger J.M.
      • Kill I.R.
      Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis.
      ) and an increased DNA damage (
      • Liu B.
      • Wang J.
      • Chan K.M.
      • et al.
      Genomic instability in laminopathy-based premature aging.
      ). In addition, keratinocytes isolated from mice with targeted expression of progerin in the skin showed higher frequency of cells with a high number of γ-H2AX foci that is indicative of DNA damage and/or impaired DNA repair mechanism (
      • Rosengardten Y.
      • McKenna T.
      • Grochová D.
      • et al.
      Stem cell depletion in Hutchinson-Gilford progeria syndrome.
      ).

      Impaired Skin Differentiation and Misregulated Gene Expression

      Mice overexpressing progerin showed halted skin development, severe inflammation, mislocalization of K5 in the suprabasal layers of the epidermis, and maintenance of lamin B receptor (LBR) in the more differentiated suprabasal layers (
      • McKenna T.
      • Rosengardten Y.
      • Viceconte N.
      • et al.
      Embryonic expression of the common progeroid lamin A splice mutation arrests postnatal skin development.
      ). This indicated that progerin expression resulted in impaired skin differentiation and a possible role for LBR in the progeroid phenotype progress. A new study carried out in our lab, in which ectopic expression of LBR was induced in mouse skin (
      • Sola Carvajal A.
      • McKenna T.
      • Wallén Arzt E.
      • et al.
      Overexpression of lamin B receptor results in impaired skin differentiation.
      ), did not recapitulate the phenotype seen in our previous model (
      • McKenna T.
      • Rosengardten Y.
      • Viceconte N.
      • et al.
      Embryonic expression of the common progeroid lamin A splice mutation arrests postnatal skin development.
      ), suggesting that LBR is not the only contributor to the progeroid phenotype. However, LBR-expressing mice also showed impaired skin differentiation with mislocalization of K5 in the suprabasal layers of the epidermis and, interestingly, downregulation of K10 that was not previously described in progeroid mice. Possibly reduced expression of K10 has been observed during normal skin aging and keratinocyte differentiation in human skin (
      • Dreesen O.
      • Chojnowski A.
      • Ong P.F.
      • et al.
      Lamin B1 fluctuations have differential effects on cellular proliferation and senescence.
      ). In these LBR-expressing mice, and lamin A G608G progeroid mice (Figure 2b and i), a high frequency of the LBR-expressing cells had a more condensed DNA distribution with increased number of γ-H2AX foci (
      • McKenna T.
      • Rosengardten Y.
      • Viceconte N.
      • et al.
      Embryonic expression of the common progeroid lamin A splice mutation arrests postnatal skin development.
      ;
      • Sola Carvajal A.
      • McKenna T.
      • Wallén Arzt E.
      • et al.
      Overexpression of lamin B receptor results in impaired skin differentiation.
      ), in agreement with another recent study that demonstrated that DNA localization and condensation can activate DNA damage response (
      • Burgess R.C.
      • Burman B.
      • Kruhlak M.J.
      • et al.
      Activation of DNA damage response signaling by condensed chromatin.
      ). Other progeroid mouse models have shown skin abnormalities. Mice lacking Zmpste24 presented progressive hair loss as well as atrophic epidermis and hair follicles and increased apoptosis (
      • Bergo M.O.
      • Gavino B.
      • Ross J.
      • et al.
      Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect.
      ;
      • Pendás A.M.
      • Zhou Z.
      • Cadiñanos J.
      • et al.
      Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice.
      ), whereas the model carrying the HGPS mouse mutation (G609G) showed a loss of the subcutaneous fat layer and of hair follicles (
      • Osorio F.G.
      • Navarro C.L.
      • Cadinanos J.
      • et al.
      Splicing-directed therapy in a new mouse model of human accelerated aging.
      ).
      • Solovei I.
      • Wang A.S.
      • Thanisch K.
      • et al.
      LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation.
      showed that LBR and lamin A mediate heterochromatin localization and tethering to the nuclear lamina in a developmental state–dependent way. Thus, heterochromatin is directly bound to the nuclear lamina and many transcription factors. As primary fibroblasts isolated from HGPS patients display loss of peripheral heterochromatin (
      • Goldman A.
      • Erdos M.
      • Eriksson M.
      • et al.
      Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome.
      ), the capacity of progerin to disrupt normal heterochromatin localization and to cause transcription factor mislocalization is therefore thought to cause the misregulated gene expression found in HGPS cell lines (
      • Csoka A.
      • English S.
      • Simkevich C.
      • et al.
      Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/ mesenchymal defects in accelerated atherosclerosis.
      ). Chromatin immunoprecipitation experiments of cells overexpressing progerin and lamin A revealed that lamin-interacting promoters lack a unique consensus binding sequence and that the expression of progerin or lamin A does not induce changes in the gene expression pattern of lamina-associated genes (
      • Kubben N.
      • Adriaens M.
      • Meuleman W.
      • et al.
      Mapping of lamin A- and progerin-interacting genome regions.
      ). However, another chromatin immunoprecipitation experiment in HGPS fibroblasts using anti-lamin A antibodies showed that nuclear disruption caused by progerin accumulation produces changes in the chromatin–lamina association, as well as redistribution of the H3K27me3 heterochromatin mark. These modifications in the nuclear architecture lead to changes in the gene expression and loss of spatial chromatin compartmentalization (
      • McCord R.P.
      • Nazario-Toole A.
      • Zhang H.
      • et al.
      Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome.
      ).

      Conclusions and Future Directions

      The emerging picture of lamin A as a part of a sensory tool for detecting forces external to the cell and relating that information to the nucleus is sure to give a greater understanding to the disease mechanisms of laminopathies. Lamin A has also been shown to have a key role in tissue stiffness and tissue matrix–directed cell differentiation, where lamin A knockdown enhanced mesenchymal stem cell differentiation on a soft matrix to low stress, fat phenotype tissues, whereas lamin A overexpression enhanced cell differentiation on stiff matrix to higher stress, bone phenotype tissues (
      • Swift J.
      • Ivanovska I.L.
      • Buxboim A.
      • et al.
      Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation.
      ). These results might explain the specificity of certain HGPS disease pathologies to tissues such as the bone or smooth muscle.
      Advances have been made in the treatment of HGPS patients in a clinical trial mainly focused in the use of farnesyl transferase inhibitor lonafarnib (
      • Gordon L.B.
      • Kleinman M.E.
      • Miller D.T.
      • et al.
      Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.
      ). This suggested improvements in vascular stiffness, and by comparing survival profiles an increased lifespan was noted (
      • Gordon L.B.
      • Massaro J.
      • D'Agostino R.B.
      • et al.
      Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.
      ).
      Future studies including the effects of lamin mutations on specific cell types, not only using appropriate models but also assessing effects on a global scale, will certainly continue to move the field forward.

      Conflict of Interest

      The authors state no conflict of interest.

      ACKNOWLEDGMENTS

      This study was supported by the Swedish Research Council, the Center for Innovative Medicine, and the Karolinska Institutet. ME is a Vinnmer fellow supported by Vinnova. This study was performed in part at the Live Cell Imaging Unit/Nikon Center of Excellence, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.

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