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NSCI 4501 > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

Neurodegenerative disorders are characterized by…

A
  • Progressive dysfunction
  • death of neurons
  • loss of white matter
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2
Q

selective vulnerability

definition

A

degeneration affects specfic systems, so not all neurons are equally vunerable

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3
Q

The two types of neurodegenerative diseases are

A
  • Cognitive Disorders
  • Motor disorders
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4
Q

Many neurodegenerative diseases have _____ types of disorder(s)

both or one

A

both

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5
Q

Neurodegenrative diseases goes hand in hand with

something that happens, could be a cause

A

protein aggregation inside and outside cells

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6
Q

Characteristics of neurodegeneration

A
  • cell death of neurons
  • process retraction
  • synaptic loss
  • synaptic dysfunction
  • protein mislocalization within synapse
  • metabolic imbalance
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7
Q

_____ ______ oppose all major changes from neurodegeneration

two words

A

homeostatic mechanisms

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8
Q

Neurons can die from

5

A
  • insufficient trophic factors (aging)
  • direct injury (TBI, Ischemia)
  • dysregulation of internal milieu (elevated Ca2+, DNA damage, ROS)
  • protein misfolding (sporadic AD & PD)
  • genetic mutations (ALS)
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9
Q

Necrosis features

8 things

A
  • Cytoplasm rupture
  • chromatin dispersion
  • loss of membrane integrity
  • quick alteration of organelles
  • no proteosynthesis
  • histone & DNA degredation
  • cellular lysis
  • inflammation
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10
Q

Apoptosis features

8 things

A
  • cellular shrings
  • chromatin condensation
  • membrane budding (membrane intact)
  • intact/unchanged organelles
  • de novo proteosynthesis
  • activation of specific endonucleases
  • apoptotic bodies
  • no inflammation
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11
Q

Necrosis is __ cell death

A

unprogrammed

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12
Q

define

Necrosis

caused by, associated with, stopped by

A
  • typically caused by exposure to high concentrations of oxidants, ionophores, or lesions
  • associated with a cytotoxic edema & cellular swelling (bc water follows Na2+ into the cell)
  • can be blocked by suppressing its stimulus
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13
Q

Synaptic NMDAR activity promotes

A

cell survival

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14
Q

Extrasynaptic NMDAR activity promotes

A

cell death

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15
Q

cell survival is promoted from

A

synaptic NMDAR activity

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16
Q

Glutamate binding to NMDAR leads to

A

increase of calcium in the cell

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17
Q

Ca2+ levels are regulated by

A

the mitochondria

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18
Q

describe

excitotoxicity

A
  1. Initiation Glu binds
  2. Amplification Ca2+ levels increase and proteases are activated. increased water in cell
  3. Expression ROS and RNA increase, production of ATP stopped, osmotic swelling
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19
Q

which death pathway when

Injury is high and calcium is high

A

Necrosis

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20
Q

death pathway when

injury is low/medium and calcium is low

A

apoptosis

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21
Q

calcium and injury levels for

necrosis

A
  • calcium medium/high if injury high
  • calcium very high if injury low
  • when both calcium and injury high
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22
Q

calcium and injury levels for

apoptosis

A
  • when injury is low, calcium low
  • when injury is high, calcium low
  • when medium injury, up to medium calcium
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23
Q

name

key molecules of neuronal apoptosis

A

Bcl-2 family proteins (Bax, Bak)
Apaf 1
Caspases

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24
Q

roles of Bcl-2 family members

A
  • Anti-apoptotic: Bcl-2, Bcl-xL
  • Proapoptotic inducers: Bax
  • Proapoptotic potentiators: Bad, Bid, Bik
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25
Q

Bcl-2 functions by

A

preventing Bax from inducing apoptosis

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26
Q

define what and define function of

Caspases

A

Cys-Asp proteases which mean they cleave motifs after Asp

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27
Q

Classification of caspases

A
  • Group I (inflammation mediator): 1
  • Group II (effector): 3
  • Group III (initiator): 8, 9
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28
Q

what it is and function

Apaf 1

A
  • apoptotic protease activating factor 1
  • transmits an apoptotic signal from mitchondria to capases
  • activated by CARD domain
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29
Q

explain

Major apoptotic pathway in neurons

A
  1. FLIP activates caspase 8
  2. Bid activates and goes into mitochondria
  3. Diablo & Cyt C released from mitochondria
  4. Cyt C binds with Apaf-1 to make apoptosome
  5. apoptosome releases caspase 9
  6. caspase 8 and 9 induce making caspase 3
  7. caspase 3 makes apoptotic substrates
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30
Q

Extrinsic apoptosis is dependent on

A
  • external receptor binding
  • caspases
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31
Q

Instrinsic apoptosis depends on

A
  • internal cellular stress
  • loss of mitochondria
  • caspases
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32
Q

Necroptosis

definition, requires, execuation

A
  • induced by death receptors
  • requires RIP1 and RIP3 activity
  • requires caspase inhibition
  • execution involves disintegration of membranes
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33
Q

steps

Execution of necroptosis

A
  1. RIP1 disassociates
  2. Na2+ increase in cell
  3. cell absorbs water
  4. edema then explodes
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34
Q

Major microfibules in axons

A

tau

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35
Q

Major microfibules in dendrites

A

MAP2

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36
Q

What regulates structure of dendritic spines

A

F-actin

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37
Q

the abnormal proteins that cause neurodegen disorders

do what

A

ruin presynaptic terminals and postsynaptic specializations

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38
Q

Mechanisms of neuronal dysfunction in Alzihmers

A
  • Gene regulation
  • cell surface receptions
  • neurotransmitter release
  • signalling cascases
  • synaptic integrity
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39
Q

Mechanisms of neuronal dysfunction in Alzihmers

A
  • Gene regulation
  • cell surface receptions
  • neurotransmitter release
  • signaling cascades
  • synaptic integrity
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40
Q

mechanisms of synaptic dysfunction

A
  • excitotoxicity
  • oxidative stress
  • inflammation
  • deregulation of proteostasis
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41
Q

ROS

produced by and causes what

A
  • produced by ETC
  • causes mtDNA muations
  • decreased ATP
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42
Q

AD is associated with a loss of

A

synapses

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43
Q

define

mitochondrial fission

A

mitochondrial renewal, redistribution and proliferation into synapses

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44
Q

define

mitochondrial fusion

A
  • mitochondiral interaction/communication with each other
  • facilitating mitochondrial movement and distribution
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45
Q

central molecules in mitochondrial fission

A
  • DRP1
  • hFIS-1
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46
Q

central molecules in mitochondrial fusion

A
  • Mfn-2
  • OPA-1
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47
Q

dysfunction of mitochondrial energy metabolism leads to

A
  • decreased ATP production
  • impaired calcium control
  • increase ROS
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48
Q

Sites of electrol leakage (superoxide generation) in mitochondira

A
  • Complex 1 of ETC
  • Complex 3 of ETC
  • TCA cycle
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49
Q

areas and examples

areas with _ contain more mitochondira

A

areas with more demands for ATP
* presynaptic and postsynaptic terminals
* active growth cones
* axonal branches
* nodes of Ranvier

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50
Q

Mitochondria are made and degraded in the

(part of neuron)

A

soma

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51
Q

3 paths for mitochondrial quality controls

A
  • degradation of misfolded or damaged proteins
  • seperate broken mitochondria through fission
  • elimination of damaged mitochodria through mitophagy
52
Q

_ is a major risk factor for neurodegenerative diseases

A

aging

53
Q

how does age and disease impact synapses?

A
  • increased ROS inactivates mitochondria
  • decreases energy/ATP
  • change in lipid structure
  • synapses can’t reuptake
54
Q

_ and _ are initiators and mediators of cell death

A

oxidative stress and disturbed energy levels

55
Q

Neuron metabolic profile

A
  • PPP favored (pfkfb3 activity low)
  • more pyruvate utilization (PDH increased)
  • no glycogen storage
  • NADPH made (increase TCA and oxidative phosphorylation)
  • M1 isoform of pyruvate kinase
56
Q

Astrocyte metabolic profile

A
  • glycolysis favored (pfkfb3 activity high)
  • glycogen stored
  • pyruvate and lactate made (decreased PDH and TCA cycle)
  • M2 isoform of pyruvate kinase
57
Q

Age is regulated by 3 independent metabolic pathways…

A
  • dietary restriction
  • the insulin/insulin-like growth factor signaling pathway (most studied)
  • the rate of mitochondrial respiration
58
Q

mTOR regulates…

A

protein synthesis

59
Q

AKT (PIP3) regulates…

A

cell survival and transcription of oxidative defense genes
* glycogen, lipid, and protein synthesis, cell survival, and the antiinflammatory response

60
Q

IGF bind to 5 receptors that then activate

A

insulin receptor signaling 1/2 (IRS-1/2)

adaptor b/w insulin receptors and mTOR, ATK, PI3K

61
Q

SOS/Grb2 (Ras) regulates

A

transcription proliferation

62
Q

define

Autophagy

A

a cytoprotective mechanism that enables the cell to survive unfavorable conditions by reducing cellular stress

63
Q

autophagic cell death is initiated when

A

mTOR is inhibited so ULK1 and Beclin 1 are activated (non-inhibited)

64
Q

Aging is a deregulator of _

A

insulin pathway

65
Q

Chaperones function

A

to make sure protein aggregates don’t have a lower energy state than other conformations for proteins

66
Q

define

proteostasis

A

protein quality control

67
Q

chaperones upregulates…

A
  • creation of proper proteins
  • degradation
  • autophagy
  • proteasome
68
Q

ATP independent HSP

A

only small HSP

69
Q

chaperones inhibits…

A
  • misfolding
  • aggregation
  • cell death
70
Q

HSP 90 is

A

an essential heat shock protein that is a hub for many cellular pathways

71
Q

Heat shock response

A

increases translation of molecular chaperones

72
Q

unfolded protein response

A

adaptive mechanisms to cope with protein folding alterations that are triggered upon ER stress

73
Q

3 adaptive UPR pathways are activated by…

A
  • IRE1 alpha -> XBP1
  • PERK
  • ATF6 -> eIF2alpha
74
Q

define

Autophagy

A

mechanism to reduce cellular stress for survival by delivering things to the lysosome for degradation

75
Q

mTOR inhibits

autophagy

A

ULK & Beclin complexes

76
Q

steps

Macroautophagy

A
  1. initiation: ULK1 makes PAS
  2. Nucleation: Beclin1 expands membrane
  3. expasion: LC3-PE forms autophagosome
  4. autophagosome taken to lysosome
77
Q

Microautophagy

A
  • invagination of the lysosomal or ednosomal membrane
  • direct engulfment of substrates
  • glutamine activates mTOR which activates RAG
  • LC3-PE (ATG8) controls
78
Q

chaperone mediated autophagy

A
  • mediated by HSC70 via LAMP2A receptor
  • HSC70 transports to LAMP2A
  • used for amino acid recylcing during starvation, quality control, and neuronal survival
79
Q

Organellophagy

A
  • receptor or ubiquitin mediated
  • Ub acts as anchor for p61 or NBR1
80
Q

PINK1-Parkin pathway

A
  • mutations in parkin cause early onset parkinson’s
  • TOM complex stoped by parkin
  • PINK binds and autophoporylates (instead of degrading
  • Ub binds, causing orgenelle autophagy
  • mitochondria degraded
81
Q

Ubiquitnation is _ dependent and used in _

A

ATP dependent and used in cytosol and nucleus

82
Q

Parkin deletions in juvenile PD causes

A

E3 ligase mutations so Ub tags can’t be put on misfolded alpha synuclein

83
Q

_ is inhibited in sporatic PD

A

26s Proteasome

84
Q

Ubiquitnation process

A
  • E1 (ub activating enzyme) binds Ub
  • E2 (ub conjugating enzyme) switches places with E1
  • E2 binds to E3 (ub ligase)
  • E3 E2 complex transfers Ub
85
Q

ERAD

A
  • ER recognizes bad proteins and sends them for proteasomal degradation
  • E3 ligase Hrd1 targets protein in cytoplasm side of ER membrane
  • Derlin extracts proteins from ER lumen
  • Ubiquitylation
  • 26S proteasom breaks down protein
86
Q

Parkinson’s often has altered

A

protein degradation mechanisms

87
Q

Amyloids

A

insoluble fibrillar protein aggregates sharing specific structural traits

88
Q

2 conformations of Amyloids

A
  • Parallel in register
  • Anti parallel out of register
89
Q

explain

aggrephagy

A

process to break down large protein aggregates and orgenelles since they are excluded from the proteasome
* requires formation of the aggresome

90
Q

formation of aggresomes requires

A
  • p62
  • HDAC6
91
Q

misfolded proteins are marked for degradation by

A

E3 Ubiquitan ligases

92
Q

Amyloid fibers are _ while soluble oligomers are _

A

stable, unstable

93
Q

Disaggregation of large amyloids is

A

slow and inefficient

94
Q

Prions are similiar to

A

smal fibril aggregates that move from cell to cell in the brain

95
Q

define

Homozygocity

A

both alleles are at the same locus

AA or aa

96
Q

define

Homozygocity

A

both alleles are at the same locus

AA or aa

97
Q

Heterzygocity

A

alleles are different at a locus

Aa

98
Q

Hemizygocity

A

only one allele is at a locus

A or a

99
Q

5 mendelian patterns

A
  • autosomal dominant
  • autosomal recessive
  • x linked dominant
  • x linked recessive
  • y linked
100
Q

factors influencing penetrance

A
  • modifier genes
  • carcinogens
  • response to DNA repair
  • hormonal factors
101
Q

factors influencing expressivity

A
  • epigentic, enviroment, aging (DNA)
  • modifier genes, miRNA (transcription)
  • snRNA, RNPs (RNA processing)
  • mTOR pathway (translation)
102
Q

familial forms of disease are caused by

A

causative genes

103
Q

sporadic forms of a disease are influenced by

A
  • susceptibility genes
  • enviromental factors
  • aging
104
Q

define

epigenetic changes

A

changes that change gene expression but not the gene sequence

105
Q

name and explain

2 types of epigenetic changes

A
  • DNA methylation usually involves methylating a cytosine residue which repressed gene activities
  • histone modification a epigenetic factor makes histodines looser and opens chromosomes
106
Q

Histones can be modified by

A
  • methylation
  • acetylation
  • phosphorylation
  • ubiquitination

these occur at specific positions

107
Q

Genome-wide association studies focus on

A

associations b/w SNPs and traits

don’t do sequencing, just identification

108
Q

Plots most often used in GWAS

A

manhattan plots
* each dot SNP
* x-axis is genomic location
* y-axis is association level

if tower is tall, big association and can pass threshold for genome wide significance

109
Q

Common problems with GWAS

A
  • lack of well difined case & control groups
  • small sample sizes
  • control for multiple testing
  • control for population stratification
110
Q

define

Odds ratio

A

represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occuring without the exposure
* in group with event: # of symptoms ÷ # of no symptom = odds of symptoms in event
* group 2 without event: # of symptoms ÷ # of no symptom = odds of symptom without event
* odds ratio: odds of symptoms in event ÷ odds of symptom without event

111
Q

When

OR = 1
OR > 1
OR < 1

A

OR = 1, exposure has no effect
OR > 1, exposore associated with higher outcome/symptoms
OR < 1, exposore associated with lower outcome/symptoms

112
Q

Transgenic mice (def and pros/cons)

A
  • extra gene added to the mouse genome
  • pros: study the effects of increased levels of a genes, effects dominant negative form of a protein, gain of function
  • cons: overexpression context, can have presence of genes from other species, chromosomal insertion effects
113
Q

Knock-in mouse

A
  • an extra gene is inserted into a specific locus
  • also uses homogologous recombination but expreses the gene
  • pros: targeted integration, study the effects of a mutant gene without overexpression, study gain and loss of function from mutations
  • cons: not able to make sure that other factors aren’t decreasing gene expression
114
Q

Knock-out mice

A
  • part of (coding) gene removed so express protein
  • targeted mutagenesis by homologous recombination
  • pros: study function in vivo and study loss of function by mutations
  • cons: gene ablation can be lethal, gene deletion can induce compensatory mechanisms, developmental phenotype, possible background strain effects
115
Q

Transgenes

A
  • developed from plasmids
  • include a promotor, coding sequence, and cDNA
  • inserted into fertilized egg which is placed in recessive homozygous female who makes a chimera
  • the chimera mates with a recessive homozygous to make fully transgenic mice founder
116
Q

TK cassette

A

destroys cells that did not go through homologous recombination properly

117
Q

the PAM sequence

A

a motif downstream of the target DNA for CRISPR

118
Q

Cre-loxP system

A
  • Cre is recombinase that combines between two LoxP sequences that are the same orientation
  • can target gene by using one mouse that has the LoxP sites around a gene and breed it with another mouse that has Cre gene with a cell specfic promotor
  • Can also yeet out a stop cassette to increase gene expression
119
Q

Tamoxifin Cre system

A

allows for triggering Cre activation at a specific time

120
Q

Cre-LoxP mice pro and cons

A
  • Pros: cell and tissue specific expression, ideal for point mutations & insertations & deletions, targeted integrations
  • cons: creation of two transgenic mouse needed, irreversible
121
Q

definition/how it works

Tet on Tet off system

A
  • modulation. ofgenen expression where transcription is turned on or off
  • dependent on the activity of an inducible transcriptional activator
  • fusion protein with Tet repressor and VP16 activation domain to create transcriptional activator protein
122
Q

in Tet-Off system: transcription is _ in the presence of Dox

A

inactive

123
Q

in Tet-On system: transcription is _ in the presence of Dox

A

active

124
Q

pros and cons

Tet-On/Off Tg mice

A

pros: tissue/cell specfic expression, temporal expression, reversible
cons: slow acting, leakage effects

125
Q

IGF bind to 5 receptors that then activate

A

insulin receptor signaling 1/2 (IRS-1/2)

adaptor b/w insulin receptors and mTOR, ATK, PI3K

126
Q

ATP independent HSP

A

only small HSP

127
Q

ATP independent HSP

A

only small HSP

NSCI 4501 (5 decks)

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