Parkinson's disease is a neurodegenerative disorder that affects movement. It results from the loss of dopaminergic neurons in the substantia nigra, which leads to a decrease in dopamine in the striatum. The main symptoms include tremors, rigidity, bradykinesia, and postural instability. Current treatment strategies include levodopa, deep brain stimulation, and stem cell therapy, but all have complications and side effects. The disease mechanisms involve oxidative stress, mitochondrial dysfunction, neuroinflammation, and the accumulation of alpha-synuclein in Lewy bodies.

1. PARKINSON’S DISEASE
Sankar Alagapan
Nov 23 2009
From A Manual of Diseases of the Nervous System:
William Gowers

2. OVERVIEW
Introduction
Disease Symptoms and Mechanisms
Pathophysiolo Molecular
Symptoms
gy Mechanisms
Treatment
Strategies
2

3. INTRODUCTION
• Neurodegenerative disease affecting movement,
cognition and other autonomic activities
• General age of onset of symptoms ~ 60 years
• Currently around 1.5 million people in the United
States with Parkinson's disease (1 in 272)
• Medication costs for an individual person with PD
average $2,500 a year, and therapeutic surgery
can cost up to $100,000 dollars per patient.
3

4. HISTORY OF PARKINSON’S DISEASE
• Kampavata - ancient Indian medical system of
Ayurveda
• Shaking Palsy – Galen (AD 175)
• 1817: Description of Symptoms - James
Parkinson
• 1862: Coined the name- Jean-Martin Charcot
• 1919: Degeneration of Substantia Nigra
Tretjakov
• 1968: First large scale results of treatment with
L-Dopa Cotzias
• 1979: MPTP induced Parkinsonism - Davis et al,
Langston
• 1997: PARK1 Gene Mutation was discovered -
Polymeropoulus
4

5. SOME FAMOUS PARKINSONIAN PATIENTS
5

6. CLINICAL FEATURES
• Motor Impairments
– Tremor at rest
– Rigidity
– Akinesia (Bradykinesia)
– Postural Deformity Jankovic 2008
– Speech and swallowing disturbances
– Gait and Posture Disturbances
6

7. CLINICAL FEATURES
• Non Motor Impairments
– Autonomic Dysfunction
• Orthostatic hypotension, sweating dysfunction,
sphincter dysfunction and erectile dysfunction
– Cognitive and Neurobehavioral Abnormalities
• Dementia, Depression, Executive Dysfunction
– Sleep Disorders
• REM Behavior Disorder
– Sensory Abnormalities
• Olfactory dysfunction, Paresthesia, Akathisia
7

8. DIAGNOSIS
• Neurologic Examination
– Unified Parkinson's Disease Rating Scale (UPDRS)
• Ioflupane – A radiological tracer for SPECT
• FDOPA and PET
8

9. PATHOPHYSIOLOGY
• Loss of dopaminergic
neurons in Substantia
Nigra pars compacta
and Locus Coeruleus
Babraham Institute Piers Emsom Dopamine and Parkinson's Disease
Madame Curie Bioscience Database
9

10. NEURODEGENERATION IN SN
• Striatum – 80% of Dopaminergic neurons
– A9 group: Substantia Nigra pars compacta (SNpc)
– A10: Ventral Tegmental Area (VTA)
• Neuromelanin in Midbrain DA Neurons
– SNpc: 84 – 98%, VTA: 50%
– Neuroprotective role in the normal brain by preferentially
sequestering pesticides, MPTP, Iron, etc.
• Vesicular Monoamine Transporter (VMAT)
– VMAT2 helps incorporating cytoplasmic dopamine in
vesicles
– VMAT2 expressed less in SNpc than in VTA
10

11. NEURODEGENERATION IN SN
• Dopamine Transporter (DAT)
– Neurotoxicity of MPTP by transporting MPP+
– Pattern of expression correlated with neuron loss
– DAT knockout mice resistant to MPTP neurotoxicity
• Calcium Binding Proteins
– Calbindin D28K (CB), Calretinin (CR), and Parvalbumin(PV)
– Administration of 6-hydroxydopamine (6-OHDA) and MPTP
results in degeneration of the CB-negative TH-positive
neurons in the SNpc, but not the TH- and CB - positive
neurons in the dorsal tier of the SNpc
• Mitochondrial DNA mutations
11

12. NEURODEGENERATION  SYMPTOMS
InDirect Pathway
Direct Pathway Globus Pallidus Internal Segment Suppression Theory
Neocortex
Hippocampus
Thalamus
Amygdala
Gpi/SNr
Striatum
GPe STN
SNpc/VTA
12

13. NEURODEGENERATION  SYMPTOMS
• Basal Ganglia Selection Theory:
– Basal ganglia are involved in the selection of
motor programs
– Bradykinesia due to failure to select or engage
appropriate motor programs
– Dyskinesia due to failure of basal ganglia to
suppress inappropriate motor programs
• Oscillator Theory
13

14. PATHOPHYSIOLOGY
• Presence of Lewy Bodies
– 1979 (Kosaka and
Mehraein)
• Lewy bodies stained
strongly with antibodies
of α – synuclein
– 1997 (Spillantini et al)
Spillantini et al 1997
14

15. α – SYNUCLEIN IN LEWY BODIES
• α-synuclein monomers
become oligomers
(protofibrils), which
coalesce into fibrils and
then aggregate into
Lewy body inclusions
• Dysfunction of
Ubiquitin Proteasome • Neurotoxic vs
System Neuroprotective
15

16. OXIDATIVE STRESS
Nigral cells seem to be under a heightened state of oxidative stress
16

17. OXIDATIVE STRESS
Nigral cells seem to be under a heightened state of oxidative stress
17

18. α – SYNUCLEIN AND OXIDATIVE STRESS
18

19. EXCITOTOXICITY
• SNc neurons receive extensive glutamate
innervation from the cortex and the
subthalamic nucleus
• Dopamine lesions disinhibit the STN and
increase the firing rate of its excitatory output
neurons
• NMDA antagonists protect against dopamine
cell loss resulting from MPP+ infusion into the
SNc of rats
19

20. CAUSATIVE FACTORS
• Neurotoxins:
– MPTP, Rotetone, 6-OHDA etc
• Genetic Factors:
– Mutations PARK1, PARK2, PARK5 etc.
• Neuroinflammation
20

21. ANIMAL MODELS
• Pharmacological Induced Models
– Reserpine
– Alpha-methyl-para-tyrosine
• Toxin Induced Models
– MPTP
– Methamphetamine
– Rotenone
– 6 OHDA
• Genetic Models
– PARK1
– PARK2
– PARK5
21

22. PHARMACOLOGICAL INDUCED MODELS
• Resperine
– First used by Carlsson (1950) in rabbits
– Showed DA depletion in caudate and putamen
resulting in akinetic state
– Led to use of Levodopa
• Alpha Methyl Para Tyrosine
– Depletes Catecholamine by inhibiting Tyrosine
Hydroxylase
• Transient Effects, No Biochemical/Pathological
Changes
22

23. TOXIN INDUCED MODELS : MPTP
• 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine
• Neurotoxicity and associated Parkinsonism
discovered in 1979 – Davis et al.
• Drug abuse by 23 year old person lead to
discovery
• Used in animal models to induce Parkinsonian
symptoms
23

24. MPTP MECHANISM OF ACTION
Dauer et al 2003 24

25. α – SYNUCLEIN AND MPTP
25

26. OTHER TOXIN INDUCED MODELS
• Rotenone:
– Naturally occurring lipophillic compound
– Specific inhibitor of Mitochondrial complex I
– Degeneration of a subset of nigrostriatal
dopaminergic neurons; the formation of cytoplasmic
inclusions; and the development of parkinsonian
motor behavior
• 6 Hydroxydopamine (6 OHDA)
– Accumulates in cytoplasm and produces ROS
– Rapid degeneration of neurons when injected in SN
– Progressive degeneration when injected in striatum
26

27. GENETIC MODELS
• Generally mutations in
the Ubiquitin
Proteasome System
• Major: Genes coding
Alpha-Synuclein, Parkin,
UCH-L1, PINK1, DJ-1
Moore 2005 27

28. GENETIC MODELS
• PARK1 (Italian and Greek families)
– A30P and A53T substitution mutations in the gene
encoding alpha-synuclein or triplicate of the gene
– Proposed to cause misfolding or dysfunction of α-
synuclein
• PARK5
– Gene encoding UCHL1 (ubiquitin C terminal
hydrolase L1)
– Generates free Ubiquitin
28

29. GENETIC MODELS
• PARK2 (Japanese Family)
– Mutation in gene encoding protein Parkin, a E3
Ubiquitin Ligase
– Ubiquitin is added to proteins by Ligase to target
them to Proteasome
– Absence of Lewy bodies in patients with
homozygous deletion shows Parkin plays an
important role in Lewy body formation
– Enable investigation of the ubiquitin-mediated
protein degradation pathways
29

30. GENETIC MODELS
Moore 2005 30

31. MOLECULAR MECHANISMS
31

32. NEUROINFLAMMATION
• Supported by Animal
Apoptosis models
– MPTP model ↑IL-1β and
Cytokines ↓NGF in striatum
TNFα,
IL-1β,
– 6-OHDA model showed
IL-6, ↑TNFα in substantia nigra
IL-2, BDNF and striatum
IL-4, NGF
TGFα,
TGF β1, • Produced from activated
TGF β2 Neurotrophins
microglia
– initially neuroprotective and
becomes neurotoxic later
32

33. TREATMENT STRATEGIES
• Drugs
– L-Dopa and Dopamine Agonists
– MAO Inhibitors and COMT Inhibitors
• Gene therapy
• Surgical Interventions
– Stem cell therapy
– Lesion surgeries and Deep Brain Stimulation
• Physiotherapy
33

34. LEVODOPA
Abbreviations:
COMT - Catechol- O-methyltransferase
3-OMD - 3-O-methyldopa
AAAD - Aromatic amino acid
decarboxylase
MAO - Monoamine oxidase
DOPAC - 3,4-dioxyphenylacetic acid
HVA - Homovanillic acid
34

35. LEVODOPA SIDE EFFECTS
Loss of Dopamine Substantial release of
Regulation DA in pulsatile fashion
Motor Fluctuations Dyskinesia
- Long Duration - Peak Dose Dyskinesia
Response and Short - Biphasic Dyskinesia
Duration Response - Square wave
- On-Off Effect - Yo-Yoing
35

36. MAO INHIBITORS AND COMT INHIBITORS
• Selegiline and Rasagiline
• Neuroprotective nature, due to propargyl
moiety, shown in vivo and in vitro
MAO Inhibitors
• Entacapone and Tolcapone
• Used in conjunction with levodopa and an
AAAD inhibitor
COMT Inhibitors
36

37. GENE THERAPY
• Genes to produce TH delivered virally (HSV) into
Dopamine striatum
Synthesis • Genetically delivered AAADC using an AAV
• Multiple genes – VMAT and TH
• Viral vectors have been used to deliver GDNF to the
striatum and SNc
Neurotrophins • In vivo lentiviral delivery of a modified neurturin
construct produced neuroprotection of rat nigrostriatal
projections.
• Lentiviral delivery to increase expression of the normal
Parkin gene in the substantia nigra of rats
Parkin Gene
• AAV carrier to deliver Hsp-70 to the substantia nigra of
MPTP-treated mice
37

38. LESION SURGERIES
• Early efforts focused on
the sensory roots of
spinal cord
• Focus then shifted to
motor cortex
• Subcortical nuclei
became areas of
interest
• Pallidotomy and
Thalamotomy
Clower 2002
38

39. LESION SURGERIES
Clower 2002
39

40. LESION SURGERIES
Clower 2002
40

41. DEEP BRAIN STIMULATION (DBS)
Targets: Thalamus, GPi, STN
Stimulation parameters: Frequency of 135 to
185 Hz, pulse width of 60 to 120 μs, and
amplitude of 1 to 3V
Wikipedia Wired.com
41

42. COMPLICATIONS ASSOCIATED WITH DBS
• Hemorrhage, ischemic lesions, seizures, infections, and
Surgical misplaced leads
Procedures • Occurrence: ~ 5%
• Electrode Failure, Lead breakage, cranial lead migration,
DBS Infection, Erosion, IPG Malfunction
Hardware • Occurrence: ~ 20%
• Eyelid apraxia, dystonic posturing, dysarthria,
dyskinesia, limb and facial muscle spasms, depression,
Stimulation mood changes, visual disturbances, and pain
• Suicide rate of 4.6% in patients with DBS.
42

43. STEM CELL THERAPY
• Hormonally induce stem cell differentiation into
nigrostriatal dopaminergic neurons or their
precursors and then to transplant them into
patients
• Embryonic stem cell (ESC) Neural Progenitor
cells (NP)
• Human NPs grafted in striatum of Parkinsonian
rats showed improvement of symptoms
• Results have also shown that mouse ESC
differentiate into DA neurons in vivo
43

44. PHYSIOTHERAPY
• Supplementary Therapy
• Help with movement, posture and balance
• Relieve muscle and joint stiffness and
discomfort
• Exercises to maintain or improve muscle
strength
44

45. PARKINSON’S DISEASE
Molecular Mechanisms Cellular Level External
Manifestations Manifestations
Neurotoxins and Oxidative PATHOPHYSIOLOGY SYMPTOMS
??
External Agents Stress Loss of Dopaminergic Movement Disorders
Genetic Factors cells in the Substantia Cognitive Decline
Neuroinflammation Nigra
Drugs, Stem Cell DBS,
Gene therapy Therapy Physiotherapy
TREATMENT STRATEGIES
Complications and Side Effects
45