Lecture 13: Parkinson's

Question 1

How many canadians have parkinson’s disease?

Answer 1

100, 000

Question 2

When do symptoms of parkinson’s usually appear?

Answer 2

age 60

Can present in much younger people

Affects 1% of population over 65

Increases to 2% in 70 or older

Question 3

Types of movements in parkinson’s

Answer 3

Resting tremor (starts in one hand as pill rolling)

Leaning forward or backward when upright

Muscle rigidity (cogwheel phenomenon - pushing on arm causes jerky movement)

Difficulty rising

Muscle rigidity

Shrinkage of handwriting

Slow movements

Loss of spontaneous movement

Question 4

What is movement controlled by?

Answer 4

signals from the motor cortex to the spinal cord (corticospinal tracts) and then to the muscles

the basal ganglia signals to the cortex (extra-pyramidal system) and affects output from the motor cortex

Corticospinal tracts run through and make up the pyramids in the medulla; extra- pyramidal system controls/modulates movement without using these corticospinal nerves

Question 5

Neuropathology of parkinson’s

Answer 5

Nigrostriatal neurons have their cell bodies in the substantia nigra and their terminals in the striatum (i.e. they release dopamine in the striatum)

Parkinson’s Disease is caused by the loss of neurons in substantia nigra, and thus, loss of dopamine innervation of striatum (part of the basal ganglia)

Symptoms appear when about 70% of nigrostriatal neurons are lost

Other neurons lost in cortex and other nuclei

Lewy bodies present (accumulation of protein)

Question 6

GABA neurons in normal person

Answer 6

GABA neurons are inhibited by dopamine and stimulated by acetylcholine

Question 7

GABA neurons in person with parkinson’s

Answer 7

Dopaminergic neurons die, leaving a relative excess of acetylcholine

Question 8

Etiology of Parkinson’s

Answer 8

actual cause is not known

metabolism of dopamine by MAO B produces free radicals (-> destroys cells?)

Environmental toxin (e.g. MPTP)

Dopamine itself – oxidant

Autophagy/lysosomal pathway (goes wrong -> low dopamine)

Mitochondrial production of free radicals (affect protein function?)

Question 9

Genetics of PD

Answer 9

Range of genetic defects

Two most common: GBA (glucosidase b, acid/glucocerebrosidase), LRRK2 (leucine-rich repeat kinase 2)

Question 10

Symptoms amenable to drug therapy in parkinson’s

Answer 10

Bradykinesia (slow initiation of movement) – Tremor at rest (“pill-rolling” movement of the hands)

Muscle rigidity (resistance to passive limb movement – cogwheel rigidity)

Abnormal posture

Early treatment for ‘neuronal sparing’

Question 11

Pharmacological targets for parkinson’s

Answer 11

Increase dopamine signaling in the brain (Corpus striatum and substantia nigra)

Decrease cholinergic activity (Striatal muscarinic receptors)

Decrease peripheral dopamine effects at D1/D2 dopamine receptors

Decrease peripheral L-DOPA metabolism

Question 12

Dopamine synthesis in substantia nigra

Answer 12

TH = tyrosine hydroxylase

DDC = dopa decarboxylase;

MAOB = monoamine oxidase B

COMT = catechol-0-methyltransferase

3-OMD = 3-0-methyldopa

See figure

Question 13

Dopamine receptors

Answer 13

G protein coupled receptors

D1 subfamily: D1 and D5 (Gs, increase cAMP)

D2 subfamily: D2, D3, D4 (Gi, decrease cAMP)

Question 14

VMAT and DAT

Answer 14

VMAT: vesicular monoamine transporter

DAT: Dopamine recycling enzyme

Question 15

What is monoamine oxidase A?

Answer 15

Enzyme that metabolizes norepinephrine and serotonin (5HT)

Question 16

What is monoamine oxidase B?

Answer 16

Metabolizes dopamine

Question 17

Dopamine synthesis and drug therapy

Answer 17

See figure

Question 18

Early treatment approach to parkinson’s

Answer 18

See figure

Note: not necessarily what happens in canada

Question 19

Non-pharmacological therapeutics for parkinson’s

Answer 19

Surgery - ablation (GPi, reduce tremor) and/or deep brain stimulation (to inhibit STN – reduce dyskinesia)

Growth factors–glial cell line-derived neurotrophic factor (GDNF)

Stem cells - replacement of dopaminergic neurons – induced pluripotent stem (iPS) cells

Question 20

iPS cells in parkinson’s

Answer 20

Convert normal fibroblast into stem cell – no need for embryonic cells; no immune rejection issues

Retroviral delivery of key genes – oct, kif, sox, myc and nanog

Select for neuronal stem cell phenotype – sox2, brn2 and nestin

Sonic hedgehog and FGF8 generated dopamine and TH +ve neurons

Integrated into striatum and corrected animal model of Parkinson’s

Caveats – induction of cancer; virus now being placed by plasmid/protein approaches

Question 21

Symptoms of parkinson’s

Answer 21

Tremor at rest but not during sleep; tremors cease or reduce when movements begin (contrast with intention tremor and essential tremor)

Muscle rigidity – unilateral or assymetric

Loss of facial expression; loss of fidgety movements

Difficulty initiating movements (e.g. getting out of chair)

Slow movements, weak voice, shuffling steps

Stooped posture, problems with balance