1. Motor Neurone DiseaseMotor Neurone Disease
Pathogenesis and potential therapeutic intervention
Professor Steven Hawking
Atypical ALS for 48 years
Lou Gehrig (1903-1941)
New York Yankees

2. ObjectivesObjectives
Introduction and clinical presentation
Is there a common cause
◦ SOD-1 folding
◦ Key to understanding sporadic forms
Pathogenesis
Potential therapeutic targets

3. Motor Neurone DiseaseMotor Neurone Disease
Common :
◦ Incidence: 2 per 100,000
◦ Prevalence: 7 per 100,000
Usually death within 3-5 years
Poorly understood disease
Diagnosed clinically
Could be collection of diseases with similar
presentation
Is there a unifying pathogenesis?

4. 4 typical patterns of MND:4 typical patterns of MND:
Amyotrophic Lateralising Sclerosis (ALS)
◦ About 60-70% of cases
Progressive Bulbar (and pseudobulbar)
Palsy
Progressive Muscular Atrophy
Primary Lateral Sclerosis
◦ V rare and not usually fatal

5. ALS – Clinical PresentationALS – Clinical Presentation
Progressive neurodegeneration
Spastic paralysis
◦ Upper and lower motor neurone signs
No sensory involvement
Typical onset 40+
Twice as likely in men

6. Familial and Sporadic ALSFamilial and Sporadic ALS
About 10% of ALS is familial
SOD-1 mutation about 20% of FALS
Unknown causes of Sporadic ALS
Is abnormal SOD-1 folding characteristic
of all ALS?
◦ Same patterns of progression
◦ mSOD-1 mice accurately model familial and
sporadic disease phenotype

7. Abnormal SOD-1 folding in SALSAbnormal SOD-1 folding in SALS
 Abnormal conformation of SOD-1 in SALS difficult to
prove with conventional immunoblot
 Biotinylation of available lysine residues can amplify
subtle changes
 Spinal cord extracts analysed (autopsy samples)
 Identification of abnormal 32-kDa (molecular weight)
biotin dependant species in both SALS and FALS
 Only 16-kDa species observed in normal subjects
(Gruzman 2007)

8. B: Prevalence of 32kDa species in normal and all ALS subjects
C: 32kDa species in SALS and FALS example (Gruzman

9. New Research – TDP-43New Research – TDP-43
Association between Frontotemporal
Lobar Degeneration and ALS
TDP-43 mislocation in both: RNA
processing
Most SALS associated with abnormal
TDP-43
Non SOD-1 mutations affect TDP-43
May provide link between SALS and
abnormal SOD-1 folding

10. Potential SOD-1 dependant pathogenesisPotential SOD-1 dependant pathogenesis
Review: Rothstein 2009

11. Therapeutic targetsTherapeutic targets
Glutamate exitotoxicity:
◦ Riluzole – 3 months prognosis improvement
Oxidative stress:
◦ Antioxidant trials (eg vit E) - little improvement
Mitochondrial damage:
◦ Permeability transition pore
◦ Disruption of ETC by Ca2+
: ROS
SOD-1 gene silencing: siRNA and antisense
(Van Damme and Robberecht 2009)
Growth factors: improve neuronal survival
Stem cells: new neurones and new glia

12.  Poorly understood disease
 Most research on mSOD-1
 Most recent drug trials target downstream
effects
 Is abnormal SOD-1 folding present in all
MND?
 Key to more focussed research and better
treatment
SummarySummary

13.  ROSEN, D. R et al 1993. Mutations in Cu/Zn superoxide-
dismutase gene are associated with familial Amyotrophic
Lateralising Sclerosis. Nature, 362, 59-62.
 GRUZMAN, A. et al 2007. Common molecular signature in SOD1
for both sporadic and familial amyotrophic lateral sclerosis.
Proceedings of the National Academy of Sciences of the United States of
America, 104, 12524-12529.
 ROTHSTEIN, J. D. 2009. Current Hypotheses for the Underlying
Biology of Amyotrophic Lateral Sclerosis. Annals of Neurology, 65,
S3-S9.
 VAN DAMME, P. & ROBBERECHT, W. 2009. Recent advances in
motor neuron disease. Current Opinion in Neurology, 22, 486-492
 MITCHELL, J. D. & BORASIO, G. D. 2007. Amyotrophic lateral
sclerosis. Lancet, 369, 2031-2041.