Motor Neurone Disease Motor Neurone Disease Pathogenesis and potential therapeutic intervention

Professor Steven HawkingAtypical ALS for 48 years

Lou Gehrig (1903-1941)New York Yankees

ObjectivesObjectivesIntroduction and clinical presentationIs there a common cause◦ SOD-1 folding◦ Key to understanding sporadic forms

PathogenesisPotential therapeutic targets

Motor Neurone DiseaseMotor Neurone DiseaseCommon : ◦ Incidence: 2 per 100,000◦ Prevalence: 7 per 100,000

Usually death within 3-5 yearsPoorly understood diseaseDiagnosed clinicallyCould be collection of diseases with similar

presentation

Is there a unifying pathogenesis?

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 AtrophyPrimary Lateral Sclerosis◦ V rare and not usually fatal

ALS – Clinical PresentationALS – Clinical Presentation

Progressive neurodegenerationSpastic paralysis◦ Upper and lower motor neurone signs

No sensory involvementTypical onset 40+ Twice as likely in men

Familial and Sporadic ALSFamilial and Sporadic ALSAbout 10% of ALS is familialSOD-1 mutation about 20% of FALS Unknown causes of Sporadic ALSIs abnormal SOD-1 folding characteristic

of all ALS? ◦ Same patterns of progression◦ mSOD-1 mice accurately model familial and

sporadic disease phenotype

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 FALSOnly 16-kDa species observed in normal subjects

(Gruzman 2007)

B: Prevalence of 32kDa species in normal and all ALS subjects C: 32kDa species in SALS and FALS example (Gruzman 2007)

New Research – TDP-43New Research – TDP-43Association between Frontotemporal

Lobar Degeneration and ALSTDP-43 mislocation in both: RNA

processingMost SALS associated with abnormal

TDP-43 Non SOD-1 mutations affect TDP-43May provide link between SALS and

abnormal SOD-1 folding

Potential SOD-1 dependant pathogenesisPotential SOD-1 dependant pathogenesis

Review: Rothstein 2009

Therapeutic targetsTherapeutic targetsGlutamate 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 survivalStem cells: new neurones and new glia

Poorly understood diseaseMost research on mSOD-1Most recent drug trials target downstream

effects Is abnormal SOD-1 folding present in all

MND?Key to more focussed research and better

treatment

SummarySummary

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.