Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the substantia nigra. Common symptoms include tremors, rigidity, and bradykinesia. Current treatments aim to replace lost dopamine, such as with L-DOPA, but long-term use can cause dyskinesia. Researchers are studying new targets like NMDA receptors and spreading of toxic alpha-synuclein aggregates to develop disease-modifying therapies that could slow progression.

1. Week 1: Parkinson’s disease

2. Outline
• Parkinson’s disease:
- Definition
- Pathology
- Symptoms
- Treatments

3. Symptoms of Parkinson’s disease
Present in the clinic with two of the following:
1. Impoverishment / slowness of movement (Bradykinesia)
2. Resting tremor
3. Muscle rigidity / Postural instability

4. A major problem with current treatments:
L-DOPA-induced dyskinesia (LID)
L-DOPA Dopamine
DOPA decarboxylase
• Currently only symptomatic treatments are available.
- usually involve replacement of lost dopamine in the form of L-DOPA
• LID caused by replacement of lost dopamine with the dopamine precursor L-DOPA

5. Progression of PD
< 50% loss of
dopaminergic neurons:
ASYMPTOMATIC
Approx. 50% loss of
dopaminergic
neurons:
MILDLY
SYMPTOMATIC
If upon diagnosis of Parkinson’s disease, it were possible to halt or prevent further cell death
patients would be able to lead a relatively normal life
< 70% loss of
dopaminergic neurons:
ADVANCED

6. Parkinson’s disease
• Most common neurodegenerative movement disorder
• Usually sporadic (10-15% genetic)
• Affects 1% population over 65 years in Western World
• - PD: Autosomal-dominant Lewy Body PD
Other
• Lewy Body disease with dementia
• Synucleopathies
Requirement: nigrostriatal degeneration

7. Hallmarks of Parkinson’s disease
Normal PD
1. Degeneration of the substantia nigra Pars compacta (SNc)
- 50% nigral neurons lost when symptoms first present

8. SNc is part of the basal ganglia……
….which is important for control of movement
dopamine
glutamate
GABA
GPl GPm
STN
Thal
PPN
SNc
cortex
thalamus
striatum
DA 2
DA 1
SNr

9. Basal ganglia circuitry is abnormal in PD
SNc
Thal
PPN
COR STR
GPl
GPm
STN
SNr
dopamine
glutamate
GABA
DA 2
DA 1

10. Hallmarks of Parkinson’s disease
2. Presence of Lewy Bodies (LB): intracellular insoluble inclusions containing a
wide variety of proteins, e.g a-synuclein, ubiquitin, neurofilament, nitrated
proteins
- Are LB toxic or their precursors toxic???
- Or are LB are a dumping ground for toxic substrates in cells???
- LBs are also found in DLB disease
- Misfolded synuclein also found in aggregates in Alzheimer’s disease

11. Pathology of Parkinson’s disease follows a pattern of spread.
Originates in the dorsal motor nucleus and olfactory nucleus
1. Dm: Dorsal IX/X motor nucleus & anterior olfactory nucleus
2. Co: coeruleus–subcoeruleus complex and brain stem
3. SN: Substantia nigra pars compacta
4. MC: Cortex, commencing with anteromedial temporal mesocortex
5. HC: neocortex e.g high order sensory association and prefrontal areas.
6. FC: Sensory association/premotor areas, primary sensory and motor fields
Braak et al., 2003: Neurobiol Aging 24: 197
motor nucleus

12. Spread is dependent on level of a-synuclein expression in
brain regions.
- also intrinisic properties of neurons governs toxicity to
degree of neurodegeneration in PD, and susceptibility to
synuclein.
• Spread of a-synuclein follows the neuronal trajectory of inter-connected
nuclei / neuronal pathways (V. Lee).
• Spares GABAergic neurons.
• Neuronal properties such as mitochondria number, excitability, neuronal
firing pattern, Na, Ca and glutamate channels, calcium binding proteins,
axonal length, axonal arborizations govern neuronal susceptibility.

13. Re-classification of Parkinson’s disease
Synucleopathies
- Any disease that shows presence of a-synuclein in
aggregated form.
- Includes idiopathic PD (caused for unknown
reasons), all genetic forms of PD, Diffuse Lewy Body
Disease, Multiple Systems Atropy?
- Idio – from Greek, coming from ones own
- Pathic – arising of a disease

14. Diffuse Lewy Body Disease vs Parkinson’s disease.
https://www.davisphinneyfoundation.org/blog/difference-lewy-body-dementia-parkinsons-
disease-alzheimers-disease/

15. Different forms of toxic a-synuclein

16. How a-synuclein spreads from cell to cell
• First discovered that synuclein aggregates can spread when LB
discovered in fetal neuronal grafts in the striatum of patients with PD.
• Spread though uptake via LAG3 receptors and Heparin Sulfate Protein
Receptors, other receptors and nanotubes.

17. Current Treatments

18. Treatments for Parkinson’s Disease
• Replacement of lost dopamine using the dopamine precursor Levo-Dopa or dopamine
receptor agonists
• - different forms of release to regulate abnormalities in dopamine levels.
• In PD, striatal dopamine metabolism is altered, leading to a tendency for levels to
fluctuate more dramatically than in healthy people.
• Adjuncts to L-DOPA, to decrease dyskinesia, gambling, hallucinates e.g. amantadine
Dopamine receptor agonists
• Miraprex – targets D3 >D2 and D4 receptors
• Side effects – gambling, increase sex drive, insomnia

19. A major problem with current treatments:
L-DOPA-induced dyskinesia
L-DOPA Dopamine
aromatic decarboxylase

20. Non-DA-ergic treatments in clinic trials /
clinic
• Amantadine (NMDA R antagonist)
• Subtype-selective NMDA receptor antagonists
• a-adrenergic receptor antagonists
• Cannabinoid receptor agonists / antagonists
• Aug 2019: The US Food and Drug Administration (FDA)
has approvedistradefylline (Nourianz, Kyowa Kirin) tablets as add-on treatment to
levodopa/carbidopa in adults with Parkinson's disease (PD) experiencing "off"
episodes.
• Istradefylline is a selective adenosine A2A receptor antagonist.
• Its effectiveness in treating "off" episodes in patients with PD taking
levodopa/carbidopa was shown in four 12-week, placebo-controlled clinical studies
that included a total of 1143 participants.

21. Non-pharmacological treatments for Parkinson’s
disease
Surgical intervention (advanced PD only)
• Pallidotomy (lesion of GPi)
• Deep brain stimulation (usually STN)
(Aboshe & Lozano (2003) Can J Neurol Sci Supp1:S72)
• Focused ultrasound (FUS) – particularly for tremor
Clinical trials
• Gene therapy
- DA cell replacement (stem cells, fetal cells)
- growth factors (BDNF; GDNF)
(Nutt et al., 2003 Neurology 14;60(1):69-73)

22. Agents in Phase III Clinical Trials