Lecture 13: Parkinson's Flashcards
How many canadians have parkinson’s disease?
100, 000
When do symptoms of parkinson’s usually appear?
age 60
Can present in much younger people
Affects 1% of population over 65
Increases to 2% in 70 or older
Types of movements in parkinson’s
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
What is movement controlled by?
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
Neuropathology of parkinson’s
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)
GABA neurons in normal person
GABA neurons are inhibited by dopamine and stimulated by acetylcholine
GABA neurons in person with parkinson’s
Dopaminergic neurons die, leaving a relative excess of acetylcholine
Etiology of Parkinson’s
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?)
Genetics of PD
Range of genetic defects
Two most common: GBA (glucosidase b, acid/glucocerebrosidase), LRRK2 (leucine-rich repeat kinase 2)
Symptoms amenable to drug therapy in parkinson’s
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’
Pharmacological targets for parkinson’s
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
Dopamine synthesis in substantia nigra
TH = tyrosine hydroxylase
DDC = dopa decarboxylase;
MAOB = monoamine oxidase B
COMT = catechol-0-methyltransferase
3-OMD = 3-0-methyldopa
See figure
Dopamine receptors
G protein coupled receptors
D1 subfamily: D1 and D5 (Gs, increase cAMP)
D2 subfamily: D2, D3, D4 (Gi, decrease cAMP)
VMAT and DAT
VMAT: vesicular monoamine transporter
DAT: Dopamine recycling enzyme
What is monoamine oxidase A?
Enzyme that metabolizes norepinephrine and serotonin (5HT)
What is monoamine oxidase B?
Metabolizes dopamine
Dopamine synthesis and drug therapy
See figure
Early treatment approach to parkinson’s
See figure
Note: not necessarily what happens in canada
Non-pharmacological therapeutics for parkinson’s
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
iPS cells in parkinson’s
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
Symptoms of parkinson’s
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
