Exam 1 Flashcards
1
Q
Neurodegenerative disorders are characterized by…
A
- Progressive dysfunction
- death of neurons
- loss of white matter
2
Q
selective vulnerability
definition
A
degeneration affects specfic systems, so not all neurons are equally vunerable
3
Q
The two types of neurodegenerative diseases are
A
- Cognitive Disorders
- Motor disorders
4
Q
Many neurodegenerative diseases have _____ types of disorder(s)
both or one
A
both
5
Q
Neurodegenrative diseases goes hand in hand with
something that happens, could be a cause
A
protein aggregation inside and outside cells
6
Q
Characteristics of neurodegeneration
A
- cell death of neurons
- process retraction
- synaptic loss
- synaptic dysfunction
- protein mislocalization within synapse
- metabolic imbalance
7
Q
_____ ______ oppose all major changes from neurodegeneration
two words
A
homeostatic mechanisms
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)
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
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
11
Q
Necrosis is __ cell death
A
unprogrammed
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
13
Q
Synaptic NMDAR activity promotes
A
cell survival
14
Q
Extrasynaptic NMDAR activity promotes
A
cell death
15
Q
cell survival is promoted from
A
synaptic NMDAR activity
16
Q
Glutamate binding to NMDAR leads to
A
increase of calcium in the cell
17
Q
Ca2+ levels are regulated by
A
the mitochondria
18
Q
describe
excitotoxicity
A
- Initiation Glu binds
- Amplification Ca2+ levels increase and proteases are activated. increased water in cell
- Expression ROS and RNA increase, production of ATP stopped, osmotic swelling
19
Q
which death pathway when
Injury is high and calcium is high
A
Necrosis
20
Q
death pathway when
injury is low/medium and calcium is low
A
apoptosis
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
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
23
Q
name
key molecules of neuronal apoptosis
A
Bcl-2 family proteins (Bax, Bak)
Apaf 1
Caspases
24
Q
roles of Bcl-2 family members
A
- Anti-apoptotic: Bcl-2, Bcl-xL
- Proapoptotic inducers: Bax
- Proapoptotic potentiators: Bad, Bid, Bik
25
Bcl-2 functions by
preventing Bax from inducing apoptosis
26
# define what and define function of
Caspases
Cys-Asp proteases which mean they cleave motifs after Asp
27
Classification of caspases
* Group I (*inflammation mediator*): 1
* Group II (*effector*): 3
* Group III (*initiator*): 8, 9
28
# what it is and function
Apaf 1
* apoptotic protease activating factor 1
* transmits an apoptotic signal from mitchondria to capases
* activated by CARD domain
29
# explain
Major apoptotic pathway in neurons
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
30
Extrinsic apoptosis is dependent on
* external receptor binding
* caspases
31
Instrinsic apoptosis depends on
* internal cellular stress
* loss of mitochondria
* caspases
32
Necroptosis
| definition, requires, execuation
* induced by death receptors
* requires RIP1 and RIP3 activity
* requires caspase inhibition
* execution involves disintegration of membranes
33
# steps
Execution of necroptosis
1. RIP1 disassociates
2. Na2+ increase in cell
3. cell absorbs water
4. edema then explodes
34
Major microfibules in axons
tau
35
Major microfibules in dendrites
MAP2
36
What regulates structure of dendritic spines
F-actin
37
the abnormal proteins that cause neurodegen disorders
| do what
ruin presynaptic terminals and postsynaptic specializations
38
Mechanisms of neuronal dysfunction in Alzihmers
* Gene regulation
* cell surface receptions
* neurotransmitter release
* signalling cascases
* synaptic integrity
39
Mechanisms of neuronal dysfunction in Alzihmers
* Gene regulation
* cell surface receptions
* neurotransmitter release
* signaling cascades
* synaptic integrity
40
mechanisms of synaptic dysfunction
* excitotoxicity
* oxidative stress
* inflammation
* deregulation of proteostasis
41
ROS
| produced by and causes what
* produced by ETC
* causes mtDNA muations
* decreased ATP
42
AD is associated with a loss of
synapses
43
# define
mitochondrial fission
mitochondrial renewal, redistribution and proliferation into synapses
44
# define
mitochondrial fusion
* mitochondiral interaction/communication with each other
* facilitating mitochondrial movement and distribution
45
central molecules in mitochondrial fission
* DRP1
* hFIS-1
46
central molecules in mitochondrial fusion
* Mfn-2
* OPA-1
47
dysfunction of mitochondrial energy metabolism leads to
* decreased ATP production
* impaired calcium control
* increase ROS
48
Sites of electrol leakage (superoxide generation) in mitochondira
* Complex 1 of ETC
* Complex 3 of ETC
* TCA cycle
49
# areas and examples
areas with _ contain more mitochondira
areas with more demands for ATP
* presynaptic and postsynaptic terminals
* active growth cones
* axonal branches
* nodes of Ranvier
50
Mitochondria are made and degraded in the
| (part of neuron)
soma
51
3 paths for mitochondrial quality controls
* degradation of misfolded or damaged proteins
* seperate broken mitochondria through fission
* elimination of damaged mitochodria through mitophagy
52
_ is a major risk factor for neurodegenerative diseases
aging
53
how does age and disease impact synapses?
* increased ROS inactivates mitochondria
* decreases energy/ATP
* change in lipid structure
* synapses can't reuptake
54
_ and _ are initiators and mediators of cell death
oxidative stress and disturbed energy levels
55
Neuron metabolic profile
* 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
Astrocyte metabolic profile
* glycolysis favored (pfkfb3 activity high)
* glycogen stored
* pyruvate and lactate made (decreased PDH and TCA cycle)
* M2 isoform of pyruvate kinase
57
Age is regulated by 3 independent metabolic pathways...
* dietary restriction
* the insulin/insulin-like growth factor signaling pathway (*most studied*)
* the rate of mitochondrial respiration
58
mTOR regulates...
protein synthesis
59
AKT (*PIP3*) regulates...
cell survival and transcription of oxidative defense genes
* glycogen, lipid, and protein synthesis, cell survival, and the antiinflammatory response
60
IGF bind to 5 receptors that then activate
insulin receptor signaling 1/2 (IRS-1/2)
| adaptor b/w insulin receptors and mTOR, ATK, PI3K
61
SOS/Grb2 (*Ras*) regulates
transcription proliferation
62
# define
Autophagy
a cytoprotective mechanism that enables the cell to survive unfavorable conditions by reducing cellular stress
63
autophagic cell death is initiated when
mTOR is inhibited so ULK1 and Beclin 1 are activated (non-inhibited)
64
Aging is a deregulator of _
insulin pathway
65
Chaperones function
to make sure protein aggregates don't have a lower energy state than other conformations for proteins
66
# define
proteostasis
protein quality control
67
chaperones upregulates...
* creation of proper proteins
* degradation
* autophagy
* proteasome
68
ATP independent HSP
only small HSP
69
chaperones inhibits...
* misfolding
* aggregation
* cell death
70
HSP 90 is
an essential heat shock protein that is a hub for many cellular pathways
71
Heat shock response
increases translation of molecular chaperones
72
unfolded protein response
adaptive mechanisms to cope with protein folding alterations that are triggered upon ER stress
73
3 adaptive UPR pathways are activated by...
* IRE1 alpha -> XBP1
* PERK
* ATF6 -> eIF2alpha
74
# define
Autophagy
mechanism to reduce cellular stress for survival by delivering things to the lysosome for degradation
75
mTOR inhibits
| autophagy
ULK & Beclin complexes
76
# steps
Macroautophagy
1. initiation: *ULK1* makes PAS
2. Nucleation: *Beclin1* expands membrane
3. expasion: *LC3-PE* forms **autophagosome**
4. autophagosome taken to lysosome
77
Microautophagy
* invagination of the lysosomal or ednosomal membrane
* direct engulfment of substrates
* glutamine activates mTOR which activates RAG
* LC3-PE (ATG8) controls
78
chaperone mediated autophagy
* mediated by HSC70 via LAMP2A receptor
* HSC70 transports to LAMP2A
* used for amino acid recylcing during starvation, quality control, and neuronal survival
79
Organellophagy
* receptor or ubiquitin mediated
* Ub acts as anchor for *p61* or *NBR1*
80
PINK1-Parkin pathway
* 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
Ubiquitnation is _ dependent and used in _
ATP dependent and used in cytosol and nucleus
82
Parkin deletions in juvenile PD causes
E3 ligase mutations so Ub tags can't be put on misfolded alpha synuclein
83
_ is inhibited in sporatic PD
26s Proteasome
84
Ubiquitnation process
* 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
ERAD
* 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
Parkinson's often has altered
protein degradation mechanisms
87
Amyloids
insoluble fibrillar protein aggregates sharing specific structural traits
88
2 conformations of Amyloids
* Parallel in register
* Anti parallel out of register
89
# explain
aggrephagy
process to break down large protein aggregates and orgenelles since they are excluded from the proteasome
* requires formation of the aggresome
90
formation of aggresomes requires
* p62
* HDAC6
91
misfolded proteins are marked for degradation by
E3 Ubiquitan ligases
92
Amyloid fibers are _ while soluble oligomers are _
stable, unstable
93
Disaggregation of large amyloids is
slow and inefficient
94
Prions are similiar to
smal fibril aggregates that move from cell to cell in the brain
95
# define
Homozygocity
both alleles are at the same locus
| AA or aa
96
# define
Homozygocity
both alleles are at the same locus
| AA or aa
97
Heterzygocity
alleles are different at a locus
| Aa
98
Hemizygocity
only one allele is at a locus
| A or a
99
5 mendelian patterns
* autosomal dominant
* autosomal recessive
* x linked dominant
* x linked recessive
* y linked
100
factors influencing penetrance
* modifier genes
* carcinogens
* response to DNA repair
* hormonal factors
101
factors influencing expressivity
* epigentic, enviroment, aging (*DNA*)
* modifier genes, miRNA (*transcription*)
* snRNA, RNPs (*RNA processing*)
* mTOR pathway (*translation*)
102
familial forms of disease are caused by
causative genes
103
sporadic forms of a disease are influenced by
* susceptibility genes
* enviromental factors
* aging
104
# define
epigenetic changes
changes that change gene expression but not the gene sequence
105
# name and explain
2 types of epigenetic changes
* **DNA methylation** usually involves methylating a cytosine residue which repressed gene activities
* **histone modification** a epigenetic factor makes histodines looser and opens chromosomes
106
Histones can be modified by
* methylation
* acetylation
* phosphorylation
* ubiquitination
| these occur at specific positions
107
Genome-wide association studies focus on
associations b/w SNPs and traits
| don't do sequencing, just identification
108
Plots most often used in GWAS
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
Common problems with GWAS
* lack of well difined case & control groups
* small sample sizes
* control for multiple testing
* control for population stratification
110
# define
Odds ratio
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
# When
OR = 1
OR > 1
OR < 1
OR = 1, exposure has no effect
OR > 1, exposore associated with higher outcome/symptoms
OR < 1, exposore associated with lower outcome/symptoms
112
Transgenic mice (def and pros/cons)
* 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
Knock-in mouse
* 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
Knock-out mice
* 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
Transgenes
* 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
TK cassette
destroys cells that did not go through homologous recombination properly
117
the PAM sequence
a motif downstream of the target DNA for CRISPR
118
Cre-loxP system
* 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
Tamoxifin Cre system
allows for triggering Cre activation at a specific time
120
Cre-LoxP mice pro and cons
* **Pros:** cell and tissue specific expression, ideal for point mutations & insertations & deletions, targeted integrations
* **cons:** creation of two transgenic mouse needed, irreversible
121
# definition/how it works
Tet on Tet off system
* 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
in Tet-Off system: transcription is _ in the presence of Dox
inactive
123
in Tet-On system: transcription is _ in the presence of Dox
active
124
# pros and cons
Tet-On/Off Tg mice
**pros:** tissue/cell specfic expression, temporal expression, reversible
**cons:** slow acting, leakage effects
125
IGF bind to 5 receptors that then activate
insulin receptor signaling 1/2 (IRS-1/2)
| adaptor b/w insulin receptors and mTOR, ATK, PI3K
126
ATP independent HSP
only small HSP
127
ATP independent HSP
only small HSP
