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BMS 114: Stem cells > Lecture 13: Parkinsons Disease > Flashcards

Lecture 13: Parkinsons Disease Flashcards

1
Q

parkinson disease is a

A

highly prevalent neurodegenerative disorder (~1% over age 60)

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2
Q

parkinsons is characterised by

A

motor dysfunction AND non-motor dysfunction symptoms

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3
Q

pathology of parkinsons:

A

DEGENERATION of dopamine neutrons in the substantia nigra (and other areas; olfactory)

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4
Q

% of people >40 yrs

A

0.4%

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5
Q

% of people >/= 65 years

A

1%

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6
Q

% of people >/= 80 years

A

10%

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7
Q

mean age at onset of parkinsons is about

A

57 years. As we live longer as a society potentially a huge healthcare burden

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8
Q

parkinsons is a neurodegenerative disease meaning its the _____ specifically..

A
  • dysfunction + death of neutrons.

- specifically - Nigrastriatal neutrons of the basal ganglia

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9
Q

in normal basal ganglia

A
  • cells of the Substantia nigra (SN) produce and release dopamine
  • dopamine from SN neutrons affects other centres
  • main centres affect = dorsal striatum (caudate nucleus & putamen)
  • dorsal striatum involved in motor function
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10
Q

what does dopamine do?

A
  • transmits signals between the areas in the brain that, when working normally, coordinate smooth and balanced muscle movement
  • may also control functions related to mood
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11
Q

dopamine precursors are

A

medications the brain converts to dopamine

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12
Q

what do antagonists do:

A

directly stimulate nerves in the brain that are not naturally being stimulated by dopamine

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13
Q

what two drugs have been prescribed to patients with Parkinsons’ and shown some effect

A
  • Dopamine precursors

- antagonists

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14
Q

what goes wrong gin Parkinson’s disease?

A
  • Cells of substantia nigra degenerate
  • these cells can no longer produce adequate amounts dopamine
  • neurons of striatum, etc. are no longer well regulated, thus do not behave in normal manner
  • results in loss of control of movements- symptoms characteristic of Parkinson’s
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15
Q

Basal ganglia: anatomy

A
  • middle of brain
  • Globus pallidus in middle
  • hearing aid like shape, putamen surrounds GP
  • caudate head to left
  • caudate body above
  • caudate tail right
  • thalamus in-between caudate and putamen
  • nucleus accumbent front bottom left
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16
Q

the basal ganglia circuitry

A
  • cortex leads to caudate & putamen (substantial nigra pars compacta [in &out])
  • Caudate & Putamen leads to Globus pallidus. leads out to Subthalamic nucleus, back to Substantia nigra Pars reticulata
  • leads to thalamus –> loops back to cortex

DRAW IT

17
Q

in parkinson’s disease, the inputs provided by the ____ ____ are diminished, meaning

A
  • Substantia nigra
  • its more difficult generate the transient inhibition form the caudate & putamen

The result of this change is the tonic inhibition from the globus pallidus is sustained to
the thalamus.
This REDUCES the thalamic excitation of the motor cortex

18
Q

characteristic symptoms: cardinal (motor) features

A
  • Slowness of movement.
  • Decreased spontaneous movements, eg eye blinking.
  • Tremors
  • Muscle rigidity
  • Postural change Gait disorders
  • slow, short steps
19
Q

non-motor symptoms

A
  • bowing of shoulders
  • swelling of feet
  • depression
  • sleep disorders
  • weight loss
  • excessice salivation
  • respiratory problems
  • orthostatic hypotension
  • increases sweating
  • constipation
20
Q

A lewy body is composed of

A

alpha-synuclein, ubiquitin, neurofilament, alpha B crystallin

21
Q

stages & symptoms:

A 
1+2 = non-motor signs 
3 = motor signs 
4,5+6 = cognition, emotion
22
Q

conventional treatments:2 types

A

medication + surgery

23
Q

medical treatment: Levodopa

A
  • (L-DOPA)
  • Precursor to dopamine, can be converted by neutrons to dopamine
  • can cross blood-brain barrier (dopamine can’t)
  • can be prescribed with carbidopa (inhibits dopamine metabolism)
  • can produce dyskinesias = uncontrolled movements among other side effects
24
Q

medical treatment: dopamine agonists

A
  • not metabolised into but act like dopamine
  • usually used with L_DOPA in round papers
  • side effects: similar to L-DOPA but less involuntary movements but can cause hallucinations
25
Q

medical treatment: MAO inhibitors & COMT inhibitors

A

these inhibit dopamine degradation, anticholinergics

26
Q

conventional treatments: surgery - Thalamotomy

A
  • destruction of small parts of the thalamus (thalamus relays messages/sensations)
  • can cause slurred speech/coordination problems
27
Q

conventional treatments: surgery - Pallidotomy

A
  • destruction of small parts of the globes pallidus

- interupts pathways between globes pallid us & thalamus

28
Q

conventional treatments: surgery - deep brain stimulation

A

implanted pace-maker like units

  • electrods placed in subthalamic nucleus
  • adv is can be turned on / off
29
Q

what about using cell replacement to treat parkinson?

A

Parkinson’s is due to a loss of a specific cell type.
Therefore: If you could transplant either
(i) Similar cells that can make dopamine or
(ii) Other calls that can make dopamine
Could you restore function?
You need : A source that can provide enough material.

30
Q

human foetal cell transplantation:

A
  • Human foetal mesencephalic tissue transplantation
  • 6-9 week-old human foetuses contain dopaminergic neutrons -These neurons can survive, re-inervate the striatum in transplanted rats.
  • First transplant into humans – 1987
  • results show increase in FDOPA uptake in putamen
31
Q

Human foetal cell transplantation trials showed

A

-increase in 17F-dopa uptake
-Re-innervation of striatum
In the most successful cases:
• L-Dopa can be withdrawn and major symptomatic recovery is seen
• Some patients had improvement 18 years post-grafting (10 years post L-dopa withdrawal)
– Proof of principle that transplantation works —

32
Q

Retinal Pigmented Epithelial Cell Transplant

A

-Dopamine-producing cells taken from pigmented retinal epithelium.
-Mechanism of transplant analagous to fetal cell transplant therapy. If loss of contact from substrate, these cells die.
Consequently, lower risk of aberrant integration—possible cause of dyskinesias seen in some FCT patients

33
Q

What about pluripotent stem cells as a source for transplantation?

A
  • PSCs can be grown in large numbers.
  • In theory could be immune –matched or from patient-derived iPS cells
  • But using hPSCs in treatment depends on two additional factors
    (i) You can differentiate the PSCs to the correct cell type, ideally efficiently.
    (ii) That the cell type you make is physiologically mature.
34
Q

how can we make dopaminergic neutrons from pluripotent stem cells?

A

PROBLEM: You have to make a particular sub- type of neuron ideally efficiently.
IN GENERAL:
To make neurons you have to
Supress mesendoderm diff i.e. promote ectoderm
Inhibit BMP and TGFbeta signalling

35
Q

Specifying midbrain dopaminergic neutrons:

A

-Neural induction is specified from the head region
-in PSC differentiation therefore anterior fates are specialised
-But if no morphogens present or FGF + Wnt inhibition you get FOREBRAIN
-WNTs, FGFs, RA are the main factors you need to CAUDALIZE the embryonic brain
Cells at the midbrain/ hindbrain boundary produce:
Wnt1 and FGF8
In particular activation of WNT signalling leads to precise patterning to FOREBRAIN, MIDBRAIN, HINDBRAIN, and ANTERIOR SPINAL CORD in a dose-dependent manner

36
Q

Dorsal-ventral patterning:

A

Shh, BMP and WNT gradients define the fat elf a neuroectodermal precursor on the D/V axis
- More Shh = more ventral fate

BMS 114: Stem cells (16 decks)

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