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Diseases of The Central Nervous System > Exam 2 > Flashcards

Exam 2 Flashcards

1
Q

What part of the brain controls movement? What if you know two different muscles at one time?

A

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

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2
Q

What is the Lewy body pathology of PD?

A

Intracellular protein aggregates composed of

Alpha-synuclein

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3
Q

What is alpha-synuclein?

A

■ 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

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4
Q

What can lead to Alpha-synuclein aggregation?

A 
■ 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)
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5
Q

How do alpha-synuclein aggregates spread?

A

Beta-sheet formation promotes aggregation
– Prion-like spread
Beta-sheets tend to be sticky and stack on each other, insoluble (bad conformation)

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6
Q

Where does PD begin and spread in the body?

A

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

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7
Q

Why is neuronal loss limited to the substantia

nigra?

A

■ 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

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8
Q

What factors likely contribute to PD?

A

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

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9
Q

What about Alpha-synuclein mutations?

A

Dominant inheritance
Mutations of alpha-synuclein are associated with early onset PD by:
-increasing the amount of gene duplications
-increasing the aggregation (point mutations)

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10
Q

LRRK2 Mutations

A

Dominant inheritance

  • Most common cause of PD
  • Large signaling protein that acts as a kinase and GTPase
  • Exact link to PD development
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11
Q

Parkin and PINK1

A

-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

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12
Q

Transgenic models of PD? Show no dopaminergic cell death? How do we compensate?

A

By chemically inducing PD using MPTP

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13
Q

What is MPTP used for?

A

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
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14
Q

How does MPTP generated PD work (mechanism).

A
  1. MPTP passes the blood brain barrier (not actually toxic to neurons)
  2. MPTP taken up by astrocytes and converted to MPP+ (now toxic to neurons)
  3. MPP+ can be transported through the dopamine transporter into neurons
  4. MPP+ binds to and inhibits mitochondrial complex 1 depleting the cell of the ability to make ATP
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15
Q

What is the cellular defense systems against ROS?

A

-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

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16
Q

What is the HTT protein?

A

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)
-

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17
Q

Cellular fates of MHTT

A

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)

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18
Q

MHTT increases excitotoxicity in neurons

A 
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
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19
Q

MHTT impairs mitochondria and axonal transport

A
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20
Q

HD treatment

A

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

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21
Q

Targeting MHTT protein

A

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

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22
Q

Botulism Toxin

A
  • sprore forming
  • Grows in warm environment
  • extremely rare, still see an issue with ameature canners
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23
Q

Food-borne symptoms

A
  • 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)
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24
Q

Botulism is rare in the US

A
  • very rare (in adults, 10 cases per year)
  • more common in infants (immune system is unprepared)
  • Symptoms- Apathy, weakened cry, loss of appetite
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25
Q

Mechanism of infection

A

Peripheral nearvous system affected
Neuromuscular junctions,
-acetycholine is released, muscle constracions
(botulism enters into nerve junctions,

26
Q

Mechanism

A

_Ganglioside
All of proteins are found
Botulism binding site is in inside vesicle, inside nerve (gets into cell by binding to two proteins(binding sites)
-endocytosis and exocytosis are linked so that you can recycle
–endocytosis is more acidic, look up acidification
-aceytocholine is brought in, gradiate is used as an energy source, exocytosis istself places proteins on ganglio on membrane surface

27
Q

Mechanism of botulism infection

A

-At a normal acetylcholine junction, comes in, activates muscle contractions, exoxytosis
1–synaptiabmine (or SV2) is bound to by botulism, so whenever it is recycled (endocytosis) into the cell, botulism gets into the cell
(acidification) 2–botulism in cell, protein pumps turns on, botulism has a pH dependent pH conformational change, pore opens, light domain leaves
-Once free in cell, acts as protease which cleaves SNARE proteins(which do vesicle fusion), once cleaved, no vesicle fusion happens.
-

28
Q

SNARE protins and fusion

A

-V SNARES (vamp)
-T-SNARES
(two negactive membranes)
In order to allow vesicle fusion V and T come together to form bundles, tighter they twist, the closer membranes come until the fuse, decreasing fusion, decreases

29
Q

Botulinum inhibits acetycholine release

A
30
Q

Treatment

A

antitoxin

  • antibody will bind to toxin, will have neutralizes which will stop binding and stop its ability to enter cell, and marophage which will eat (absorb) toxin
  • Will only work on toxins that are not in the cell, regeneration of nerve terminals takes 2-8 works (cell makes more snare proteins and little walking dude has to walk them down nerve which could take awhile)
31
Q

Other applications

A

-can be used to reduce wrinkles, help with excess sweating,

32
Q

Tetanus

A

You also have a pH confromational change

33
Q

Tetanus symptoms

A

-muscle spasms, can’t real;y swallow,

34
Q

Mechanism of infection

A
  • Starts at nueromuscular junctions, binds to ganglioside, and goes into cell, does not get released (not active in acetycholine cell), It gets retrogradely transported back to the cell body,
  • Dynein walks back
  • Excited the original cell that was infected and moves to gaba cell where the cleavage starts
  • Cleaves VAMP proteins, which causes increase stimulation of acytecholine because you have removed an inhibitory structure,
35
Q

Tetanus Mechanism

A

-GABA can’t be released so more acytocholine is released into cell

36
Q

Tetanus treatment

A
  • Still gets everything outside the cell
  • GABA agonist is also treatment to decrease the amount of muscle spasms, if caught early it is completely reversible
  • Also a vaccine
37
Q

Human Immunodeficiency VIrus

A

HIV is one of the most common virus worldwide

38
Q

Anti-retrovial therapy

A

Extendes the life of those affected with HIV

39
Q

Overall HIV infections are decreasing

A
  • Due to education
  • originally was a lot of stigma
  • Number one was is through intercouse, without a condom,
  • Passed from mother to baby, birth and also through breast milk
  • Drug use through sharing injecting equipment,
  • Have been cases of contaminated blood transfusions and organ transplants
40
Q

You Cant get HIV from—-

A

Kissing (peck, though french kissing if any blood), hugging, sharing food, insect bites, toilet seats, bathing, sneezes and coughs, sweat
HIV not in saliva

41
Q

Can’t prevent HIV by_____

A

Washing after sex, having sex with only virgins, pulling out method, spells and herbal medicine, using the contraceptive pill

Condoms and PrEP used correctly consistently protect you from HIV transmission during sex

42
Q

Viral Host

A

-life cycle
Hiv infects CDA+T (helper T cells, have memory)
Helper T cells active the rest of immune system, they activate B cells, and your cytotoxic T cells (they recognize a cell that is already infected)
Also

43
Q

Acute HIV infection (symptoms)

A

-fever, sores in mouth, muscle ackes, headache, fougyness

44
Q

HIV progression to Aids

A

Once you go below 200 CD4+T helper cells, AIDS

45
Q

HIV-Associated Neurocognitive Disorder (HAND)

A

HIV enters the brain early in infection
10% of individuals have a neurocognitive problem as a presenting symptom

Cognition- Impairments in attention, processing speed, working memory, executive functioning (hypocampus, frontal lobe

Motor- Unstead Gait, poor coordination, tremor (cerebellum, basal gaglia,)

Behavior- Apathy, depression, anxiety, agitation, mania, sleep distrubance (amygdulla)

46
Q

Antiviral development has greatly decreased HAND

A

Not many people exibit any neurocognitive abnormalities,
-Asymptomatic- has to be in two ways, doesn’t interfer with daily life
-Mild- interferes with a little bit but not much
-

47
Q

HIV can enter the brain

A

Enters brain through breakdown of Blood Brain Barrier

48
Q

HIV weakens the blood brain barrier

A
  • Endothelial cell surround blood, forms vesicle
  • In blood brain barrier endothelial cells dont have gaps (tight junctions) the interlock and create tight barrier, also have pericyte (help with maintain)
  • Astrocyte
49
Q

BBB Breakdown

A

starts with infected monocyte, it crosses the bbb, starts shedding HIV
-microglia recognize HIV so they release cytocine, causes inflammation in brain, they have a CDA+T so they can get infected, if infected, they don’t get lysed so life long,
Increased inflammation causes neuroal damage and cell death

50
Q

HIV astrocytes

A

-this is restricted, they can get into astrocytes
occurs in a CD4-independent manner
HIV can’t get released from astrocytes but does cause inflammation
can also inhibit reuptake of glutamate, leads to exocytoxisity, more action potentials getting fired,
part of BBB which disruptive,
Lysosome function is affected , cant remove debre from cell

51
Q

HIV entry limited in CNS

A

can’t affected neurons and oligodendrocytes, however increased exitotoxicity and inflammation can affected both

52
Q

Neuronal damage

A

viral replication is occuring, releasing cytokines, excitotoxicity, inflammation

53
Q

Neuronal specific

A

Viral proteins associated with HIV, have shown to affected neurons
Gp120-

Tat-

Nef-

54
Q

How does HIV get into the brain

A

Monocyte carries HIV into the cell

55
Q

HIV treatment

A

Anti viral, extremely difficult to development with no side effects to cell

  • Integrated into host DNA, potentially might have to deal with blood brain barrier
  • would have to prevent some of the cell from functioning,
56
Q

With HIV, where in the life cycle would you target to stop the disease.

A

Inhibit reverse transcriptase (this is something that the virus brings in)
Prevent from entering the host cell (inhibit GP120(
Inhibit CCR5
Inhibit integrase protein brought by HIV

57
Q

Prions: Protein Folding

A

-Protein folding determines function
-misfolded proteins do not function properly and are prone to aggregation
in order from protein to function, they have a particular shape

58
Q

Prion Disease

A

-Neurodegenerative diseases characterized by the deposition of a misfolded isoform of proin protein in the CNS
named on how they are transmitted and the animal they are in

59
Q

Prion protein

A

Normal: PrPc

Diseased: PrPsc (larger domain is primairaly beta sheets, prone to aggregation

60
Q

Prion protein trafficking

A

-membrane associataed protein, clingses to lipid raft,

frequently endocytosis

61
Q

Conversion and Aggregation

A

Can hace conversion is normal one into misfolded

this happens by unnormal associating with normal

62
Q

CJD

A

Variant- getting sick from transfering from one to another
Familial- very rare
Latrogenic- like someone had surgery and the tools werent cleaned the best

Diseases of The Central Nervous System (3 decks)

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