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 ( )

3. CAG = glutamine (Q)

5. 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)

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

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

8. 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 Bunina bodies
Jacob-Creutzfeldt prion Prions
(mad cow disease)

9. Towards Therapy

10. Normal cell in the body DNA (genes) Protein Messenger RNA
The central dogma of biology
DNA – RNA- protein
Protein is essential for basic biological function and participate in every process that happens inside the cell

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

12. 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

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

14. RNA interference targets the messenger
DNA
(genes)
protein

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

16. RNAi as a therapy for SCA7X
Trafficking defects
Therapy targets in
SCA7 X
mutant atx7