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Nuclear lamins and laminopathies

Nuclear lamins and laminopathies. - What is lamin A ? - LAMINOPATHIES Drug discovery platform: Lamin A and aging Prelamin A processing and drugs acting on it Structure of the platform DIATHEVA’s antibodies unique performance. Version 01-06-11. INDEX. WHAT IS LAMIN A?.

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Nuclear lamins and laminopathies

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  1. Nuclear lamins and laminopathies • -What is lamin A? • - LAMINOPATHIES • Drug discovery platform: • Lamin A and aging • Prelamin A processingand drugs acting on it • Structure of the platform • DIATHEVA’s antibodies unique performance Version 01-06-11

  2. INDEX WHAT IS LAMIN A? Lamin A is the major component of the nuclear lamina and supports many nuclear functions. Alterations in lamin A gene, protein or maturation pathway have been associated with: • Laminopathies, agroup of inherited disorders in which Lamin A gene is mutated; • Tumours, because aberrant expression of A-type lamins is a marker of differentiated tumour cells and seems to be a marker of good or poor patient survival; • Aging, since it has been hypothesized a shared mechanism between pathological and physiological process; • Anti-retroviral therapy, involving the use ofprotease inhibitors (PIs). Some HIV-PIs lead to the onset of a secondary laminopathy through the inhibition of ZMPSTE24, the enzyme responsible for prelamin A maturation.

  3. INDEX LAMINOPATHIES • Emery-Dreifussmusculardystrophy • Limb-girdlemusculardystrophy • Familiancardiomyopathywithconduction system disease • Charcot-Marie-Toothperipheralneuropathy • Dunningan-typefamilianpartiallipodystrophy • Mandibuloacraldysplasia • RestrictiveDermopathy • Hutchinson-Gilford progeria syndrome • AtypicalWerner’s syndrome • Atypicalprogeroidsyndrome • (Progeroidsyndromes) Accumulation of Prelamin A Worman H.J. Et al., (2010), CSH Perspectives Andrés V. et al., (2009), The Journal of Cell Biology

  4. INDEX Drug discovery platform 50 aa deletion CSIM PROGERIN Farnesyl LAMIN A AND AGING Abnormal RNA splicing occurring in HGPS cells takes place at very low levels in normal cells. Accelerated aging in HGPS might reflect an exaggerated lamin A-dependent mechanism, which normally contributes to physiological aging1-3. HGPS patients Healty old individuals C>T EXO 12 EXO 11 EXO 12 EXO 11 LMNA mRNA Sporadic use of the activated cryptic splice site Constitutive use of the activated cryptic splice site Low levels of toxic truncated lamin A High levels of toxic truncated lamin A ≈10 YEARS ≈70 YEARS • Alteration of nuclear lamina structure • Disorganization of heterochromatin • Histone modifications • Accumulation of unrepaired DNA damage 1Coutinho H.D. et al., (2009) Immunity & Ageing 2McClintock D. et al., (2007) Plos One 3Navarro C.L. at al., (2006) Human Molecular Genetics

  5. INDEX Drug discovery platform • A new platform in drug discovery for: • Laminopathies and Progeroid Syndromes • Aging • Anti-retroviral therapy • The platform includes: • Polyclonal antibodies • Recombinant proteins • PCR kits for direct sequencing of the involved genes • Prelamin A processing Cell-Free System Immunoassay

  6. INDEX Drug discovery platform SH RSY-LLGNSSPRTQSPQNCSIM COOH SIM COOH S COCH3 LLGNSSPRTQSPQNC RSY-COOH Drugsacting on prelamin A processing A CAAX motif PRELAMIN A Farnesyltransferase Inhibitors (FTI) treatment causes reversion of the nuclear blebbing and improving of the nuclear shape in HGPS fibroblasts1. Several clinical trials for laminopathies are currently ongoing evaluating the effects of FTI, statins andbisphosphonates. Farnesylation FTI STATINS BISPHOSPHONATES S RSY-LLGNSSPRTQSPQNCSIM COOH B Cleavage by endoprotease (Zmpste24 or RCE1) S C RSY-LLGNSSPRTQSPQNC Methylation • HIV Protease Inhibitors (HIV-PIs)Lopinavir, Ritonavir and Tipranavir interfere with prelamin A processing by blocking ZMPSTE24 • others HIV-PIs show no or little effect on the enzyme activity (Atazanavir, Amprenavir. Darunavir)2. S D RSY-LLGNSSPRTQSPQNC COCH3 HIV-I PIs cleavage by Zmpste24 E MATURE LAMIN A 1Yang S. H. et al., (2010) J Lipid Res. 2Hudon S.E. at al., (2008) Biochem Biophys Res Commun.

  7. INDEX Drug discovery platform Human fibroblasts accumulating farnesylated prelamin A (or progerin) Human fibroblasts accumulating non-farnesylated prelamin A anti-prelamin A antibody anti-cleaved-farnesylatedprelamin A antibody DIATHEVA’s antibodies can be used to discriminate which prelamin A forms are accumulated in laminopathic or drug-treated cell samplesand to test the efficacy of any type of drug acting on the prelamin A maturation pathway Dominici S. et al., (2009), European Journal of Histochemistry

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