Pathogenesis of Parkinson's disease

1. Pathogenesis of Parkinson's disease • Free Radicals and Deficits in Energy Metabolism • Programmed cell death •
Genetic factors • Environmental factors • Protein aggregation • Aging • Drug-induced parkinsonism Barreto GE,
Iarkov A, Moran VE. Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson's
disease..
2. Pathogenesis of Parkinson's disease Farooqui T, Farooqui AA. Lipid-mediated oxidative stress and inflammation in
the pathogenesis of Parkinson's disease. Parkinsons Dis. 2011 Feb 15;2011:247467.
3. Pathogenesis of Parkinson's disease • Free Radicals and Deficits in Energy Metabolism – The most common
cellular free radicals are hydroxyl radical (OH•), superoxide radical (O2 ̄•), and nitric oxide (NO•). Other
molecules, such as hydrogen peroxide (H2O2) and peroxynitrite (ONOO ̄) are not free radicals but can lead to the
generation of free radicals through various chemical reactions. – Dopamine, as a relatively unstable molecule in
nature, undergoes auto-oxidation metabolism in the nigrostriatal tract system thereby producing ROS.
4. Pathogenesis of Parkinson's disease • Free Radicals and Deficits in Energy Metabolism Free radical • Proteins 
Thiol oxidation & carboxyl formation  activation/ deactivation of enzyme • Lipid  Lipid peroxidation 
Membrane damage • DNA  Altered gene expression  depletion of ATP and NAD(P)H Cell injury / inflammation
ROS↑ NF-kB Nfr2 NF-KB / Nfr2 mediated gene expression NEURODEGENERATION SYMPTOMS of PD
5. Pathogenesis of Parkinson's disease • Programmed cell death – Dopaminergic degeneration in the substantia nigra
may cause PD. – Caspases are a family of protease enzymes playing essential roles in programmed cell death
(including apoptosis, pyroptosis and necroptosis) and inflammation. Caspase dependent Caspase independent
Apoptosis (PCD type I) Autophagic cell death (PCD type II) Necroptosis (PCD type III) Healthy cell
6. Pathogenesis of Parkinson's disease Refer: Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015 Aug
29;386(9996):896-912. • Environmental Factors & Genetic Factors
7. Environmental Factors • Repeated injection of MPTP (1-methyl-4phenyl- 1,2,3,6-tetrahydro-pyridine) causes PD. •
Pesticides such as rotenone and paraquat leads to oxidative and nitrative stress which leads to lead to greater risk of
developing PD. • Smokers and coffee drinkers have been associated with a lower risk of PD. Pathogenesis of
Parkinson's disease
8. Protein aggregation: Pathogenesis of Parkinson's disease • Proteins are essential and it is playing diverse roles in all
living organisms. • Proteins folding and aggregate through several stages eventually assembling into fibers, and
such nonfunctional protein aggregates can be toxic. • All misfolded proteins share a common structural feature,
known as the “amyloid fold.”
9. Aging: – Age itself is not likely to play a direct role in the degenerative process, but increased age is a risk factor
for PD. – Possible role of aging in the pathogenesis of PD is usual occurrence in late middle age (loss with age of
striatal DA and DA of cells in the substantia nigra). Pathogenesis of Parkinson's disease
10. Aging: Pathogenesis of Parkinson's disease Reference: Reeve A, Simcox E, Turnbull D. Ageing and Parkinson's
disease: why is advancing age the biggest risk factor? Ageing Res Rev. 2014 ;14:19-30.
11. Drug-induced parkinsonism: – Many drugs can cause parkinsonian symptoms; these effects are usually reversible.
– The most important drugs are the butyrophenone and phenothiazine antipsychotic drugs, which block brain
dopamine receptors. – At high doses, reserpine causes similar symptoms, presumably by depleting brain dopamine.
Pathogenesis of Parkinson's disease
12. Drug-induced parkinsonism: Pathogenesis of Parkinson's disease Class of drug causing parkinsonism Example
Typical antipsychotics Chlorpromazine, Prochlorperazine, Fluphenazine, Promethazine, Haloperidol Atypical
antipsychotics Risperidone, Olanzapine, Ziprasidone, Aripiprazole Dopamine depleters Reserpine, Tetrabenazine
Antiemetics Metoclopramide, Levosulpiride, Clebopride Calcium-channel blockers Flunarizine, Cinnarizine Drug
infrequently causing Parkinsonism: Clozapine, Quetiapine, Lithium, SSRIs, valproic acid, phenytoin, domperidone,
itopride