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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 processing and drugs acting on it Structure of the platform DIATHEVA’s antibodies unique performance Version

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, a group 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 of protease 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 Accumulation of Prelamin A
INDEX LAMINOPATHIES Emery-Dreifuss muscular dystrophy Limb-girdle muscular dystrophy Familian cardiomyopathy with conduction system disease Charcot-Marie-Tooth peripheral neuropathy Dunningan-type familian partial lipodystrophy Mandibuloacral dysplasia Restrictive Dermopathy Hutchinson-Gilford progeria syndrome Atypical Werner’s syndrome Atypical progeroid syndrome (Progeroid syndromes) Accumulation of Prelamin A Worman H.J. Et al., (2010), CSH Perspectives Andrés V. et al., (2009), The Journal of Cell Biology

4 LAMIN A AND AGING Drug discovery platform
INDEX Drug discovery platform 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. EXO 11 EXO 12 C>T LMNA mRNA Constitutive use of the activated cryptic splice site HGPS patients Sporadic use of the activated cryptic splice site Healty old individuals High levels of toxic truncated lamin A Low levels of toxic truncated lamin A ≈10 YEARS ≈70 YEARS 50 aa deletion CSIM Farnesyl PROGERIN 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 Drug discovery platform
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 Cleavage by endoprotease (Zmpste24 or RCE1)
INDEX Drug discovery platform CAAX motif RSY-LLGNSSPRTQSPQNCSIM COOH SH A Drugs acting on prelamin A processing PRELAMIN A FTI STATINS BISPHOSPHONATES Farnesylation 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 and bisphosphonates. B RSY-LLGNSSPRTQSPQNCSIM COOH S Cleavage by endoprotease (Zmpste24 or RCE1) SIM COOH 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 LLGNSSPRTQSPQNC S COCH3 E RSY-COOH MATURE LAMIN A 1Yang S. H. et al., (2010) J Lipid Res. 2Hudon S.E. at al., (2008) Biochem Biophys Res Commun.

7 anti-prelamin A antibody anti-cleaved-farnesylated prelamin A antibody
INDEX Drug discovery platform Human fibroblasts accumulating non-farnesylated prelamin A Human fibroblasts accumulating farnesylated prelamin A (or progerin) anti-prelamin A antibody anti-cleaved-farnesylated prelamin A antibody DIATHEVA’s antibodies can be used to discriminate which prelamin A forms are accumulated in laminopathic or drug-treated cell samples and 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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