advances in polyglutamine disease research & therapy albert la spada, m.d., ph.d. professor of...
TRANSCRIPT
![Page 1: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/1.jpg)
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 PediatricsAssociate Director, Institute for Genomic Medicine
NAF meetingMarch 18, 2011
![Page 2: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/2.jpg)
Advances in molecular genetics fueled a decade (or so) of discovery (1988-2000)
![Page 3: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/3.jpg)
CAG = glutamine (Q)
![Page 4: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/4.jpg)
![Page 5: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/5.jpg)
CAG / polyglutamine repeat diseases
Spinal & bulbar muscular atrophyHuntington’s diseaseDentatorubral 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)
![Page 6: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/6.jpg)
SCA7 pedigree (UWMC Neurogenetics Clinic)
d. 16 yo
d. 63 yo
d. 80 yo
38 yo 36 yo
- presented with visual problems at age 6; developed ataxia, went blind, cognitive decline
- dysarthria, ataxia,and central scotoma
48 CAGs
- blind, walks with cane; 50 CAGs
- presented at age 50with visual problems;ataxia / spasticity
- presented with coordination problem in her late 60s
?
Example ofANTICIPATION
= worsening of disease phenotype in
successive generations
![Page 7: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/7.jpg)
...CAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG...
DNA sequence = trinucleotide repeat expansion
…QQQQQQQQQQQQQQQQQQQQQQQ...
Amino acid sequence = glutamine tract expansion
Protein product = misfolded conformation
![Page 8: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/8.jpg)
Formation of protein aggregates in neurodegeneration: a common link
Disease Implicated protein Histopathology
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)
![Page 9: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/9.jpg)
Towards Therapy
![Page 10: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/10.jpg)
Normal cell in the body
DNA (genes)
Messenger RNA
Protein
![Page 11: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/11.jpg)
Cell affected By SCA7
Abnormal DNA
Incorrectmessage
Protein
Toxic
![Page 12: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/12.jpg)
Andrew Fire and Craig Mello won the Nobel Prizein 2006 for their discovery of RNA interference
Andrew Fire
Stanford University
Craig Mello
University of Massachussets
![Page 13: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/13.jpg)
Round wormsPetunias
RNA interference was first discovered in plants and worms
![Page 14: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/14.jpg)
RNA interference targets the messenger
DNA(genes)
Messenger RNA
protein
Interfere
![Page 15: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/15.jpg)
RNA interference is a promising therapy for many different diseases:
1. Huntington’s disease
2. Other degenerative brain disorders
3. Cancer
4. HIV
![Page 16: Advances in polyglutamine disease research & therapy Albert La Spada, M.D., Ph.D. Professor of Pediatrics and Cellular & Molecular Medicine Division Chief](https://reader036.vdocuments.mx/reader036/viewer/2022062721/56649f1f5503460f94c3791e/html5/thumbnails/16.jpg)
RNAi as a therapy for SCA7
RNAi
XTrafficking defects
mutant atx7X Therapy
targets inSCA7