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

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

CAG = glutamine (Q)

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)

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

...CAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG...

DNA sequence = trinucleotide repeat expansion

…QQQQQQQQQQQQQQQQQQQQQQQ...

Amino acid sequence = glutamine tract expansion

Protein product = misfolded conformation

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)

Towards Therapy

Normal cell in the body

DNA (genes)

Messenger RNA

Protein

Cell affected By SCA7

Abnormal DNA

Incorrectmessage

Protein

Toxic

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

Round wormsPetunias

RNA interference was first discovered in plants and worms

RNA interference targets the messenger

DNA(genes)

Messenger RNA

protein

Interfere

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

XTrafficking defects

mutant atx7X Therapy

targets inSCA7