1. Parkinson’s Disease Paul Tuite, MD University of Minnesota Director of Movement Disorders

2. Parkinson’s disease (PD) Early Clinical Features Tremor Slowness Stiffness Stooped posture Altered gait Small handwriting Softened voice Others

3. Epidemiology of PD Incidence –5-24/ 10 5 worldwide (USA: 20.5/10 5 ) –Incidence of PD rising slowly with aging population Prevalence –57-371/10 5 worldwide (USA/Canada 300/10 5 ) –35%-42% of cases undiagnosed at any time Onset –mean PD 62.4 years –rare before age 30; 4-10% cases before age 40 www.wemove.org

4. Risk Factors Definite: Old age Highly likely: MZ co-twin with early-onset PD Probable: Positive family history Possible: Herbicides, pesticides, heavy metals, proximity to industry, rural residence, well water, repeated head trauma, etc. Possible protective effect: Smoking www.wemove.org

5. Black line is age related loss A.Toxin causes rapid loss of neurons at exposure B.Genetic cause with variable rates of loss of neurons depending on the gene C.Genetic and toxic model A H V Schapira; BMJ 1999;318:311-314

6. Genetics of PD PARK1: (dominant), 4q21: alpha-synuclein PARK2: (mainly recessive) 6q25-q27: Parkin PARK3: (dominant, reduced penetrance) 2p13 PARK4: (dominant, early onset) 4p15 PARK5: (susceptibility gene) 4p14: UCH-L1 PARK6: (recessive) 1p35-p36 PARK7: (recessive) 1p36 PARK8: (dominant) 12p11 PARK9: (Kufor-Rukeb syndrome; recessive) 1p36 PARK10: (susceptibility gene) 1p32 FTDP17: (susceptibility gene) 17q21: Tau

7. The Scientist 1997

8. PD & Environmental Factors Increased Risk –Pesticides Paraquat Organochlorines Carbamates –Welding –Miners Decreased Risk –Coffee consumption ?Caffeine –Smoking Nicotine –MAO B inhibition –CYP2D6

9. GeneticsEnvironment Mitochondria Complex I Defects Protein Accumulation Oxidative Stress Excitotoxicity Abnormal Protein Degradation Cell Death Betarbet et al. Brain Path 2002;12:499-510.

10. Mitochondria

11. Complex I Mitochondrial Inhibitors Betarbet et al. Brain Path 2002;12:499-510.

12. ROTENONE

13. Betarbet et al. Brain Path 2002;12:499-510.

14. GAO 2003 inflamm in PD TIPS

15. Neurorestoration Neuroprotection Rate of development of disease A H V Schapira; BMJ 1999;318:311-314 THERAPIES UNDER DEVELOPMENT