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Advances in polyglutamine disease research & therapy

Advances in polyglutamine disease research & therapy. Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief of Genetics, Dept. of Pediatrics Associate Director, Institute for Genomic Medicine. NAF meeting March 18, 2011.

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Advances in polyglutamine disease research & therapy

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  1. Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief of Genetics, Dept. of Pediatrics Associate Director, Institute for Genomic Medicine NAF meeting March 18, 2011

  2. Advances in molecular genetics fueled a decade (or so) of discovery (1988-2000)

  3. CAG = glutamine (Q)

  4. CAG / polyglutamine repeat diseases Spinal & bulbar muscular atrophy Huntington’s disease Dentatorubral pallidoluysian atrophy Spinocerebellar ataxia 1, 2, 3, 6, 7 & 17 • all affect the nervous system • all are dominant (except SBMA which is X-linked) • all comparable median ages of onset • all are slowly progressive • all show a correlation between increasing expansion size and disease severity - this correlation + tendency of the repeats to expand when transmitted from parent to child explains:ANTICIPATION • all are caused exclusively by CAG repeat expansions that are translated into polyglutamine tracts (except SCA6)

  5. - presented with coordination problem in her late 60s - presented at age 50 with visual problems; ataxia / spasticity - presented with visual - blind, walks - dysarthria, ataxia, problems at age 6; with cane; and central scotoma developed ataxia, went 50 CAGs 48 CAGs blind, cognitive decline SCA7 pedigree (UWMC Neurogenetics Clinic) d. 80 yo Example of ANTICIPATION = worsening of disease phenotype in successive generations ? d. 63 yo 38 yo d. 16 yo 36 yo

  6. DNA sequence = trinucleotide repeat expansion ...CAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG... Amino acid sequence = glutamine tract expansion …QQQQQQQQQQQQQQQQQQQQQQQ... Protein product = misfolded conformation

  7. Formation of protein aggregates in neurodegeneration: a common link DiseaseImplicated proteinHistopathology CAG / polyQ Various Nuclear inclusions diseases (e.g. HD) Alzheimer’s dz APP, apoE, others Neurofibrillary tangles & beta-amyloid plaques Parkinson’s dz synuclein, others Lewy bodies ALS (Lou Gehrig’s) TDP-43 Bunina bodies Jacob-Creutzfeldt prion Prions (mad cow disease)

  8. Towards Therapy

  9. Protein Messenger RNA Normal cell in the body DNA (genes)

  10. Cell affected By SCA7 Protein Incorrect message Abnormal DNA Toxic

  11. Andrew Fire and Craig Mello won the Nobel Prize in 2006 for their discovery of RNA interference Andrew Fire Stanford University Craig Mello University of Massachussets

  12. Round worms Petunias RNA interference was first discovered in plants and worms

  13. RNA interference targets the messenger Interfere Messenger RNA DNA (genes) protein

  14. RNA interference is a promising therapy for many different diseases: • Huntington’s disease • 2. Other degenerative brain disorders • Cancer • 4. HIV

  15. RNAi X RNAi as a therapy for SCA7 Trafficking defects Therapy targets in SCA7 X mutant atx7

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