Lecture 7: Parkinson's Disease Flashcards
(38 cards)
Describe the timeline for genetic forms of P.D.
Tends to occur earlier in life (sometimes when the patients are in their 20s and 30s).
How did James Parkinson describe the motor disorder of PD?
involuntary tremulous motion with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards and to pass from a walking to a running pace, the senses and intellects being uninjured.
What is PD?
Degeneration of dopamine producing neurons in the substantia nigra
The axons of the dopaminergic neurons project to the striatum (caudate + putamen) and synapse on medium spiny neurons).
What are the cardinal symptoms of PD?
-Resting tremor (arm might shake at specific frequency)
-Slowness of movement (bradykinesia)
Rigidity Difficulty initiating movement (chronic muscle spasms).
- Paucity of spontaneous movements
-70% of patients eventually also develop dementia.
How many people in the US are affected by PD (approximately)?
1.5 million Americans
In PD there is a massive ____ in levels of the neurotransmitter dopamine
1) reduction
What are some causes and risk factors of PD?
-Genetics
-Pesiticde exposure (example paraquat)
-Oxidative stress (byproduct of normal cell function)
-Age
Describe the additional PD pathology of Lewy Bodies
Levy bodies appear as spherical masses that displace other cell components. They are primarily composed of fibrillar aggregates of the presynaptic protein alpha-synuclein
Majority of patients have Lewy bodies
Describe a-synuclein
-Primary component of Lewy bodies
- A53T mutation: Alanine becomes a Threonine at position 53 of the alpha synuclein protein. A30P and E46K also causes PD
-Duplication of the a-synuclein gene can also cause PD
-a- synuclein appears susceptible to aggregation much like beta amyloid in AD.
1) Aggregate is toxic to cell
2) Aggergate stops healthy function
It is involved in dopamine signaling
1% of all proteins in the brain.
Function remains unclear.
But presynaptic locatilizaiton is associated with membranes and vesicles.
Mouse a-synuclien knockouts are relatively normal but suggest a role in synaptic vesicle recycling and dopamine signaling.
How can we model PD?
- Transgenic mouse models
-Using stem cells from patient to model PD
-Neurotoxic lesions (6-OHDA, MPTP, Rotenone)
Describe the frozen addicts: MPTP Story
In 1979 a grad student attempted to synthesize meperidine, a synthetic opiate and accidentally created an impurity: MPTP.
MPTP is metabolized in the brain to MPP+ and taken up specifically by dopaminergic neurons
MPP+ kills dopaminergic cells in the midbrain that project to the basal ganglia
Result: Highly advanced PD.
What is the onset of symptoms like for normal PD patients vs. MPTP+ patients?
PD: slow onset 1-2 years before symptoms show
MPTP+: Overnight
What are the symptoms of MPTP+ induced PD?
Burning sensation, frozen, inability to speak
Why did MPTP end up becoming an useful tool for research purposes?
MPTP is quite specifically metabolized into toxic MPP+ and taken up by and kills dopaminergic neurons.
This was used to quickly induce PD in mice.
Describe the 3 critical cellular functions that are affected by PD familial mutations.
Almost all genetic mutations and toxins associated with PD effect one or more of these 3 critical cellular functions:
Mitochondria
Proteasomes
Autophagy
Describe the role of mitochondria.
-Generate energy (ATP) for all cells from glucose and oxygen.
-Neurons that are most most active need more mitochondria (ex. motor proteins).
-Create harmful reactive oxygen species (ROS) as a byproduct of energy production. ( This byproduct can damage mitochondria, proteins, DNA or RNA).
-ROS and other mitochondrial signals can induce cell death.
Describe the role of proteasomes
-Degrade unwanted or misfolded proteins.
-Cells ‘tag’ unwanted or old proteins for proteasomal degradation by adding chains of the protein ubiquitin to them.
- Ex. a-synuclein is normally degraded by the proteasome.
(Issues with proteasomes = build up of alpha synuclein).
Describe the role of autophagy.
- Degrades protein aggregates or old difunctional organelles.
-Mitochondria only last about 20 days before they become damaged and need to be replaced. - Mitophagy is another term for the degradation of mitochondria via autophagy.
Impair ability to get rid of faulty mitochondria if problems with autophagy.
Describe the L-DOPA therapy for PD
L-DOPA
Helps the brain make more dopamine but it is difficult to regulate the levels of dopamine so it often causes side effects such as Dyskinesia
-Increase efficiency to make more dopamine.
- Dyskinesia: uncontrollable movements due to L-DOPA
Over time however, L-DOPA becomes less effective.
Describe Deep Brain Stimulation therapy for PD
a method of treatment in which a surgically implanted device delivers electrical pulses to particular parts of the brain. It is used to reduce tremor and to block involuntary movements in patients with motion disorders, by inhibiting overexcitement in the thalamus (especially in the treatment of multiple sclerosis) or the globus pallidus (especially in the treatment of Parkinson’s disease).
It is very effective for a subset of patients.
Typically those that are younger
Current therapies do not halt or alter the disease progression, True or False?
True
Potential uses of stem cells in PD
-Using stem cells to replace lost dopaminergic neurons.
- Using stem cells to protect vulnerable host dopaminergic neurons.
-Determining the placement of stem cells is an important aspect to consider as well.
-Should we put them where they belong?
-Should we put them in the target region.
If you want a replacement of dopamine where do you put stem cells?
Substantia Nigra
If you want nutrients/ more indirect effects of the stem cells where do you put them?
Target region
