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ana 410G > exam 3 > Flashcards

exam 3 Flashcards

1
Q

what is gene silencing? where does it operate and what does it eliminate?

A
  • a method designed to lower the expression of disease-causing genes (protein knock-down)
  • operates upstream of protein production
  • eliminates the mRNA coding for the targeted and unwanted protein
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2
Q

gene silencing works by:

a) killing the messenger rna
b) attacks the proteins produced by the gene
c) stops the dna transcription for the disease-causing gene
d) damages the ribosome from translating the mRNA

A

a) killing the messenger rna

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3
Q

what are the two methods used for gene silencing?

A

RNA interference and antisense oligonucleotides

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4
Q

what is RNAi?

A

a mechanism of gene silencing when double-stranded RNA disrupts the normal processing of mRNA for a protein, leading to the degradation of the mRNA, preventing translation and stopping protein expression.

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5
Q

what are the two approaches for RNAi?

A

viral vector encoding short hairpin RNAs (AAV-shRNA) and synthetic small interfering RNAs (siRNAs)

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6
Q

key advantages of AAV-shRNA (4)

A

-mild immune response
-expression of dna is long lasting
-chronic silencing can be achieved
-no need for chronic administration

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7
Q

what are AAV-shRNAs

A

short hairpin DOUBLE stranded rna complementary to mrna for the disease causing protein delivered via viral vector

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8
Q

key obstacles of AAV-shRNA (2)

A
  • regulation of gene expression is unreliable
  • gene silencing can’t be reliably controlled
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9
Q

place the steps of the AAV-shRNA mechanism in order:

a.shRNAs get processed into smaller double stranded siRNAs by dicer
b. the sense strands dissociate from RISCs
c. AAV-shRNA injection, followed by shRNA transcription inside the cell
d. siRNAs assemble into endoribonuclease-containing complexes known as RISCs
e. siRNA-mediated target recognition
f. activated RISCs cleave and destroy RNA to achieve gene silencing

A

c,a,d,b,e,f

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10
Q

what is siRNA

A

synthetic short DOUBLE stranded rna molecules that have one complementary strand to disease causing protein

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11
Q

key obstacles of siRNA (3)

A
  • poor cellular uptake
  • stability is short lived
  • requires chronic administration
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12
Q

key advantages of siRNA (2)

A
  • gene silencing can be controlled
  • more potent/lower dose needed than ASOs
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13
Q

place the steps in order for the mechanisms of siRNA:

a. siRNA mediated target recognition
b. administration of stable double stranded siRNAs conjugated to lipids
c. activated RISCs cleave and destroy RNA to achieve gene silencing
d. siRNAs assemble into RISCs
e.the sense strands dissociate from RISCs

A

b,d,e,a,c

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14
Q

what are antisense oligomers (ASOs)?

A
  • a mechanism of gene expression where normal mRNA processing is disrupted by SINGLE stranded RNA causing degradation of the disease causing protein
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15
Q

key obstacles for ASOs (4)

A
  • stability is short lived
  • cellular uptake is difficult
  • requires chronic administration
  • less potent than siRNA
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16
Q

key advantage for ASOs (1)

A

gene silencing can be controlled

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17
Q

put the steps of ASOs mechanism in order:

a. the antisense-RNA hybrid is recognized as aberrant and cleave by enzyme RNase H
b. presence of antisense blocks initiation of translation by ribosomes causing gene silencing
c. hybridize to a complementary are of mRNA by forming a short area of double strands
d. administration of synthetic ASOs

A

d,c,a,b

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18
Q

AAV-shRNAs initiate RNA interference by activating which ribonuclease protein?

a.BMP-4
b. RISC
c. FGF-8
d. RNaseH
e. DICER

A

e. DICER

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19
Q

key obstacles of sheeps and mini pigs used for HD research (4)

A

-longer gestation time
-longer time to reach puberty
-breeding is slow and expensive
-do not express phenotype or neuropathological characteristics of HD

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20
Q

key advantages of using non-human primates for HD research (4)

A

-larger brain size
- basal ganglia neuroanatomy is comparable to humans
- express motor and cognitive deficits, and enlarged lateral ventricles
- neuropathology of Htt aggregates and extensive neuronal loss

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21
Q

key obstacles of using non-human primates for HD research (4)

A

-long gestation time
-long time to reach puberty
-breeding is slow and expensive
-only few HD non-human primates

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22
Q

key advantages of using rodents for HD research (4)

A
  • short gestation time
  • short time to reach puberty
  • breeding is quick and inexpensive
  • develop motor deficits, neurodegeneration, and pathological changes (high mutant Htt levels, nuclear aggregates of mutant Htt in striatum, and cortical and striatal atrophy)
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23
Q

key obstacles of using rodents for HD research (2)

A

-smaller brain size
-different neuroanatomy than humans

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24
Q

what causes HD?

A

a gene mutation resulting in the expression of an abnormally long version of Htt due to an expanded CAG segment (>36 nucleotides is toxic)

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25
Q

what does it mean for HD to have autosomal dominant inheritance

A

a single abnormal allele inherited from one parent is enough to cause HD

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26
Q

describe which two brain regions are most affected in HD

A
  • mutant Htt causes increase in rate of neuronal degradation in striatal medium spiny neurons (GABA) and frontal cortex (GLU)
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27
Q

describe the identifying feature of pathology in HD

A
  • enlarged lateral ventricles
  • increased CSF volume
  • decreased striatal volume
  • loss of spiny neurons in striatum (motor fxn)
  • neuronal loss in frontal cortex (emotions and thinking)
28
Q

describe the diagnosis tests and methods of HD for symptomatic and presymptomatic individuals

A
  • confirmatory/symptomatic testing using clinical exams, genetic screening, family history, and neuroimaging
  • pre-symptomatic testing using family history and genetic screening
29
Q

which of the following statements concerning HD is INCORRECT?

a. HD is caused by a gene mutation
b. HD is an autosomal dominant inherited disease
c. HD mainly affects the cerebellum
d. HD can be diagnosed using DNA testing from a blood sample

A

c. HD mainly affects the cerebellum

30
Q

describe the main symptoms of HD (3)

A
  • motor impairments (chorea, lack of coordination, slurred speech, sleep issues)
  • cognitive impairments (executive functions, memory impairment)
  • psychiatric impairments (depression, paranoia, compulsive behavior, suicide)
31
Q

describe current HD treatments for symptoms (3)

A
  1. cognitive and psychological - antidepressants/antipsychotics
  2. motor - Tetrabenazine - reduces chorea
  3. daily exercise, high calorie healthy nutrition, speech and physical therapy
32
Q

what are the symptoms of PD

A

motor symptoms: resting tremor, gait disturbance, bradykinesia, rigidity
non-motor symptoms: constipation, urinary dysfunction, dermatitis

33
Q

describe the pathology of PD

A

dysfunction of nigrostriatal dopaminergic system
- >50% degeneration of dopamine producing neurons in substantia nigra pars compacta

34
Q

explain the behavioral response to apomorphine and d-amphetamine in animals unilaterally lesions with 6-OHDA (turn direction, frequency of turns, side of DA release)

A
  • apo produced rotation behavior contralateral to the lesion (turns away from lesion- left/right) and 3-5 turns/min, DA released on non-lesioned side
  • dAMPH produced rotations ipsilateral to the lesion (turn toward lesion- right/right) and 5-14 turns/min, DA released on lesioned side
35
Q

explain the mechanism of formation of alpha-sinuclein oligomer toxicity

A

a-synuclein is naturally occurring protein but when its beta sheet configuration becomes misfolded, oligomers and aggregates form and can leat to lewy body or spread to unaffected cells causing cell death

  • believed to start in GI tract***
36
Q

what are limitation of the two animal models compared to the presentation of PD in humans

A

-6OHDA rat model only presents motor symptoms of PD (streetlight effect)
- alpha synuclein animal model doesn’t reflect all patients bc not all PD patients have high a-synuclein and there’s lots of variability within the preparation of the drug treatments

37
Q

damage to the nigrostriatal system on one side causes which side to present motor dysfunction in PD patients?

A

contralateral side

38
Q

describe L-DOPA treatment and why it differs from dopamine

A

-dopamine can’t pass thru BBB but L-dopa can
L-dopa treatment:
- reduces motor dysfunction
- doesn’t prevent dopaminergic neuron degeneration
- lots of side effects

39
Q

a patient arrive in clinic and has a history of PD. Which symptom do u NOT expect this patient to have?

a.resting tremor on the most affected side
b. absence seizures
c. slow movement of fingers
d. difficulty walking
e. stiffness in arms and neck

A

B. absence seizures

40
Q

explain the 6-OHDA toxicity mechanism in PD rat model.

A

6-OHDA is taken up by DAT and generates free radicals that kills dopamine neurons causing mitochondrial dysfunction and oxidative damage

41
Q

You were recently hired to work in a PD lab to conduct behavioral testing in rats previously administered 6-OHDA to the right SN. You are asked to asses the severity of the lesion by injecting d-AMPH to the animals. Assuming a successful 6-OHDA lesion; describe the behavioral response you are expecting to observe in these d-AMPH treated animals?

a.contralateral rotation behavior due to dopamine release on lesioned side
b. bilateral rotation behavior
c. ipsilateral rotation behavior due to DA release on non-lesioned side
d. ipsilateral rotation behavior due to dopamine release on lesioned side
e. contralateral rotation behavior due to dopamine release on non-lesioned side

A

c. ipsilateral rotation behavior due to DA release on non-lesioned side

42
Q

what are the major neuronal systems involved in PD

A

basal ganglia
- striatum (putamen and caudate nucleus)
- dopamine pathways
- substantia nigra (nigro-striatal pathway)

43
Q

give examples of drug therapy options for PD and their risks

A
  1. levodopa - long term motor and acute cognitive adverse effects
  2. direct dopamine agonists (ritigotine) - moderate efficacy, acute side effects, and can cause behavioral changes
44
Q

what are some believed risk factors/causes of PD

A

aging, genetics, tbi, military service combat, rural living, well water, pesticides, viruses

45
Q

describe the symptom relationships for ON and OFF medications/symptoms caused by Levodopa for the following:

  1. Off/Off
  2. Off/On
  3. On/Off
  4. On/On
A
  1. off drug, off movement = early stage PD
  2. off drug, on movement = normal person
  3. on drug, off movement = later stage PD
  4. on drug, on movement = early stage PD
46
Q

what are some future treatment strategies for PD

A
  • improve diagnostic accuracy, symptomatic management, and treatment of complications
  • treat non-motor manifestations
  • slow disease progression
  • diagnose earlier
47
Q

what are the basic symptoms of MS

A

sensory changes, weakness, vision loss, ataxia, diplopia

48
Q

what patient groups are at risk for MS

A
  • females are 2-3x more likely than men
  • increased risk until age 35
  • some genetic factor risks
49
Q

what are the three subtypes for MS

A
  • benign MS
  • relapsing remitting MS (most common type)
  • secondary chronic MS
  • primary progressive MS (can’t treat - 10/20%)
50
Q

what are the different world populations at risk for MS

A
  • increased prevalence in northern countries (away from equator)
  • strong association with vitamin d deficiency, infectious agents like ebv
51
Q

why is MS treatment a success story for neurology and how treatment has affects concepts of clinical trial design

A

interferon beta injections (disease modifying therapies) set the standard for clinical trials as they were effective in improving disease progression, not just symptom alleviation.

52
Q

what is the DSM-5 criteria for Substance use disorders

A

impaired control, social impairment, risky use, pharmacological criteria, took out legal consequences

53
Q

what are the different types of major substance use disorders and potential liabilities for each

A

nicotine, opioids, alcohol, stimulants, cannabis

54
Q

describe the neuroscience research for mechanisms of addiction (DA and GLU)

A
  • dopamine receptors are important for the 4 reward pathways
  • glutamate plays a major role in HPC and PFC function
55
Q

how does neuroscience guide us in treatments for addiction

A

research has shown us:
- prevention of teen drug abuse is a good investment
- medications that modulate DA and GLU may give some benefit for drug abusers

56
Q

what are the current trends for the use of different controlled substances

A

DRD4-7R receptor, ADHD, and higher reward dependency from increased internet addiction

57
Q

how is severity of SCI graded clinically by ASIA (A-E)

A

A - complete injury/ no sensory or motor function
B- incomplete injury/ some sensory, no motor
C- incomplete injury/ some sensory, sever motor loss
D- incomplete injury/ some sensory, some motor loss
E. normal

58
Q

Describe the different locations of injury and how they affect function outcomes (tracts)

A

descending tracts (motor)
- lateral/ventral corticospinal tract = motor
ascending tracts (sensory)
- dorsal columns= deep touch, proprioception, vibration
- lateral spinothalamic tract= pain/temp
- ventral spinothalamic tract= light touch

59
Q

what causes motor, sensory, and autonomic deficits after SCI

A

Damage to:
- ascending tracts causes sensory deficits
- descending tracts causes motor deficits
- sympathetic/parasympathetic nerves cause autonomic deficits

60
Q

how does a neuron detect axon injury

A

lesions cause translation of importin-B to protein which induced formation of the importin heterodimer, creating a high-affinity NLS binding site associated with dynein. This creates a signaling cargo to transport the injury signal to the nucleus

61
Q

what are neuron-intrinsic factors that regulate axon growth and give an example

A

change with neuronal age
- intracellular growth signalling pathways
- receptor expression
- energy

62
Q

what are neuron-extrinsic factors that regulate axon growth and give an example

A

differential expression during development, maturation or injury states
- extracellular matrix
- chemoattractive/repulsive factors
- inhibitory proteins

63
Q

give examples of experimental manipulations that can stimulate axon regeneration

A
  • reactive astrocytes can support axon growth from production of neurotrophic factor CNTF
  • genetics may play a role
  • combinatory experiments may work best
64
Q

Describe the different locations of injury and how they affect function outcomes (spinal vertebrae)

A
  • cervical= tetraplegic (below neck)
  • thoracic= paraplegic (trunk/lower body)
  • lumbar= paraplegic (below the belt)
  • sacral= paraplegic (feet/back of legs/butt)
65
Q

continual retraction of the growth cone due to no growth supportive environment results in….

A

dystrophic growth cones

ana 410G (11 decks)

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