Transcript No Slide Title

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
Advances in molecular genetics fueled
a decade (or so) of discovery (1988-2000)
CAG = glutamine (Q)
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)
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
- blind, walks
with cane;
50 CAGs
d. 63 yo
38 yo
36 yo
- dysarthria, ataxia,
and central scotoma
48 CAGs
d. 16 yo
- presented with visual
problems at age 6;
developed ataxia, went
blind, cognitive decline
DNA sequence = trinucleotide repeat expansion
...CAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG...
Amino acid sequence = glutamine tract expansion
…QQQQQQQQQQQQQQQQQQQQQQQ...
Protein product = misfolded conformation
Formation of protein aggregates in
neurodegeneration: a common link
Disease
CAG / polyQ
diseases (e.g. HD)
Implicated protein
Various
Alzheimer’s dz
APP, apoE, others
Parkinson’s dz
synuclein, others
Histopathology
Nuclear inclusions
Neurofibrillary tangles
& beta-amyloid plaques
Lewy bodies
ALS (Lou Gehrig’s)
TDP-43
Bunina bodies
Jacob-Creutzfeldt
(mad cow disease)
prion
Prions
Towards Therapy
Normal cell in
the body
DNA
(genes)
Protein
Messenger
RNA
Cell affected
By SCA7
Abnormal
DNA
Protein
Toxic
Incorrect
message
Andrew Fire and Craig Mello won the Nobel Prize
in 2006 for their discovery of RNA interference
Andrew Fire
Craig Mello
Stanford University
University of Massachussets
RNA interference was first discovered in plants and worms
Petunias
Round worms
RNA interference targets the messenger
Interfere
DNA
(genes)
Messenger
RNA
protein
RNA interference is a promising therapy for
many different diseases:
1. Huntington’s disease
2. Other degenerative brain disorders
3. Cancer
4. HIV
RNAi as a therapy for SCA7
RNAi
Trafficking defects
X
mutant
atx7
X
Therapy
targets in
SCA7