Exam 2 Flashcards
(62 cards)
What part of the brain controls movement? What if you know two different muscles at one time?
Willful movements originate in the primary cortex.
The more fine muscles part of cortex controls, larger portion (hands and face movement take up most of cortex),
When you put together different muscle movements, basal ganglia starts to act as a processing center to integrate multiple different signals from different places
What is the Lewy body pathology of PD?
Intracellular protein aggregates composed of
Alpha-synuclein
What is alpha-synuclein?
■ Function not fully elucidated
■ Thought to play a role in synaptic transmission
– Interaction with SNARE complexes
Mice with a-synuclein deletion have increased neurotransmitter
release
a-synuclein is inhibiting signal
What can lead to Alpha-synuclein aggregation?
■ Aggregation enhanced by – overexpression of protein – Malfunction of protein degradation (protease system -embiquadine- proteasome chops up protein of target. (if this is inhibited, makes things hard to degrade, overexpression)
How do alpha-synuclein aggregates spread?
Beta-sheet formation promotes aggregation
– Prion-like spread
Beta-sheets tend to be sticky and stack on each other, insoluble (bad conformation)
Where does PD begin and spread in the body?
Lewy body starts in the gut,
One theory is that PD starts in gut (Vagus nerve takes to brain), explains constipation and loss of smell
Why is neuronal loss limited to the substantia
nigra?
■ Spiny neurons of the SN are highly branched and receive excitatory
signals from multiple sources
– Frequent depolarization
Frequent depolarization might be what makes them more sensitive then surrounding cells
What factors likely contribute to PD?
Environmental factors
- oxidative stress
- mitochondrial damage
- excitotoxicity
Genetic Factors
- A-synuclein
- LRRK2
- PINK1
- Parkin
- DJ-1
- UCH-L1
—-genetic factors can lead to altered conformation, proteasome dysfunction, and protein aggregation
All lead to cell death
What about Alpha-synuclein mutations?
Dominant inheritance
Mutations of alpha-synuclein are associated with early onset PD by:
-increasing the amount of gene duplications
-increasing the aggregation (point mutations)
LRRK2 Mutations
Dominant inheritance
- Most common cause of PD
- Large signaling protein that acts as a kinase and GTPase
- Exact link to PD development
Parkin and PINK1
-Act in the same pathway- mutations in either have same effect
-Necessary for mitophagy to occur
–In PD mutations prevent the removal of damaged and malfunctioning mitochondria
PINK1– causes dimerization and autophosphorylation
–Parkin and activation leads to membrane formation around the mitochondria and degradation of the organelle through the lysosome
Transgenic models of PD? Show no dopaminergic cell death? How do we compensate?
By chemically inducing PD using MPTP
What is MPTP used for?
To chemically induce PD
- Leads to death of dopaminergic neurons
- -Used to test effectiveness of PD treatments
- Shortcomings- not a gradual loss of neurons as seen in human PD, Lewy bodies are absent
How does MPTP generated PD work (mechanism).
- MPTP passes the blood brain barrier (not actually toxic to neurons)
- MPTP taken up by astrocytes and converted to MPP+ (now toxic to neurons)
- MPP+ can be transported through the dopamine transporter into neurons
- MPP+ binds to and inhibits mitochondrial complex 1 depleting the cell of the ability to make ATP
What is the cellular defense systems against ROS?
-Antioxidants
Vitamins C and E
-Mitochondrial enzymes
-Cytosolic enzymes -Glutathione peroxidase and catalase
If the cellular defenses are overwhelmed, then cells undergo apoptosis
-80% of dopaminergic neurons must die before clinical motor symptoms present
What is the HTT protein?
About 300 in length
No homology to other proteins (nothing to compare it too)
■ All over neuron, in cytoplasm, Associates with the Golgi, ER, nucleus, synapses and vesicles
■ Nuclear export signal- may aid in nuclear transport, traffic in/out of nucleas, might have some funtion associated with this
■ HEAT repeats aids in protein-protein interactions,
■ Many sites for post-translational modifications, change function of protein (pulonamalation)
■ Germline deletion is lethal- important in development (important for development of embryo, not in adult tho)
-
Cellular fates of MHTT
Protease cleavage- where conformation actually happens, beta sheet (leads to abnormal aggregation)
Adding unbiquitan- breaks up peptide bonds to be reused
Autophagy- recruit vesicles to form membrane sack around what needs to be degraded, sack fuzes to lysosome
If neither occur, you get aggregation
(HTT can leave one cell and travel to another by extracellular travel)
MHTT increases excitotoxicity in neurons
mutant MHTT causes an excitotoxicity, calcium activates and cleaves many macromolecules NMDA receptor(on post-synaptic receptor) is one way calcium enters the cell, calcium can also act as a second messenger), astrocyctes normal take up glutamate to recycle it, keeps balance) MHTT has shown to increase extrasynaptic protein downstream cell causes cell death
MHTT impairs mitochondria and axonal transport
HD treatment
Is not a cure and only helps one symptom, reduces chorea by either inhibiting dopamine from being transported, another way on postsynaptic cell, the receptors are blocked
Targeting MHTT protein
trying to reduce mutant huntingtons
Oligonnucleotides bind to RNA, makes cell recognise as doublestranded RNA which is not possible and cell’s cleave mRNA of huntington’s protein synthesize.
Only doing treatments to figure out if they can deliver it
Deliver lumbar punctures, painful and expensive
Botulism Toxin
- sprore forming
- Grows in warm environment
- extremely rare, still see an issue with ameature canners
Food-borne symptoms
- some type of paralysis
- Can have some localized or be wide spread
- control of smooth muscles in affected, peristalsis is affected along with muslce weakness
- Tachycardia respiratory paralysis (unable to control diaphram)
Botulism is rare in the US
- very rare (in adults, 10 cases per year)
- more common in infants (immune system is unprepared)
- Symptoms- Apathy, weakened cry, loss of appetite
