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Nuclear lamins and laminopathies - What is lamin A?What is lamin A - LAMINOPATHIESLAMINOPATHIES -Drug discovery platform: -Lamin A and agingLamin A and.

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Presentation on theme: "Nuclear lamins and laminopathies - What is lamin A?What is lamin A - LAMINOPATHIESLAMINOPATHIES -Drug discovery platform: -Lamin A and agingLamin A and."— Presentation transcript:

1 Nuclear lamins and laminopathies - What is lamin A?What is lamin A - LAMINOPATHIESLAMINOPATHIES -Drug discovery platform: -Lamin A and agingLamin A and aging -Prelamin A processing and drugs acting on itPrelamin A processing and drugs acting on it -Structure of the platformStructure of the platform -DIATHEVA’s antibodies unique performanceDIATHEVA’s antibodies unique performance Version

2 Laminopathies, Laminopathies, a group of inherited disorders in which Lamin A gene is mutated; Tumours, 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, Aging, since it has been hypothesized a shared mechanism between pathological and physiological process; Anti-retroviral therapy, 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. 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: WHAT IS LAMIN A? INDEX

3 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)  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 INDEX

4 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 aging 1-3. EXO 11 EXO 12 C>T LMNA mRNA Constitutive use of the activated cryptic splice site HGPS patients EXO 11 EXO 12 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 Drug discovery platform LAMIN A AND AGING 1 Coutinho H.D. et al., (2009) Immunity & Ageing 2 McClintock D. et al., (2007) Plos One 3 Navarro C.L. at al., (2006) Human Molecular Genetics INDEX

5 drug discovery A new platform in drug discovery for: -Laminopathies and Progeroid SyndromesLaminopathies and Progeroid Syndromes -AgingAging -Anti-retroviral therapyAnti-retroviral therapy drug discovery A new platform in drug discovery for: -Laminopathies and Progeroid SyndromesLaminopathies and Progeroid Syndromes -AgingAging -Anti-retroviral therapyAnti-retroviral therapy The platform includes: -Polyclonal antibodiesPolyclonal antibodies -Recombinant proteinsRecombinant proteins -PCR kits for direct sequencing of the involved genesPCR kits for direct sequencing of the involved genes -Prelamin A processing Cell-Free System ImmunoassayPrelamin A processing Cell-Free System Immunoassay Drug discovery platform INDEX

6  HIV Protease Inhibitors (HIV-PIs)  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. Farnesylation Methylation Cleavage by endoprotease (Zmpste24 or RCE1) cleavage by Zmpste24 MATURE LAMIN A CAAX motif RSY-LLGNSSPRTQSPQNCSIM COOH SH A C D PRELAMIN A Drug discovery platform B RSY-LLGNSSPRTQSPQNCSIM COOH S SIM COOH RSY-LLGNSSPRTQSPQNC S S CO CH 3 E LLGNSSPRTQSPQNC S CO CH 3 RSY- COOH Drugs acting on prelamin A processing FTI STATINS BISPHOSPHONATES HIV-I PIs  Farnesyltransferase Inhibitors (FTI)  Farnesyltransferase Inhibitors (FTI) treatment causes reversion of the nuclear blebbing and improving of the nuclear shape in HGPS fibroblasts 1.  FTI, statins bisphosphonates  Several clinical trials for laminopathies are currently ongoing evaluating the effects of FTI, statins and bisphosphonates. 1 Yang S. H. et al., (2010) J Lipid Res. 2 Hudon S.E. at al., (2008) Biochem Biophys Res Commun. INDEX

7 Human fibroblasts accumulating non-farnesylated prelamin A anti-prelamin A antibody anti-cleaved- farnesylated prelamin A antibody Human fibroblasts accumulating farnesylated prelamin A (or progerin) 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 Drug discovery platform INDEX


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