Exam one study guide Flashcards
- What are the six share mechanisms in neurodegenerative diseases?
“P- PRION”- mnemonic
1. Protein Aggregation
2. Protein Degradation
3. RNA mediated toxicity
4. Impaired axonal transports
5. Oxidative Stress
6. Neuronal Cell Death
damage or death of neurons caused by excessive stimulation of the glutamate receptors (NMDA)
excitotoxicity
ALP regulates energy balance and plays a pro‐survival role **T/F Q
original function of the autophagy-lysosomal pathway
– Q: does ALP mediate cell death?
A: F
Does oxidative stress always lead to neurodegeneration **T/F Q
-No, only when free radical concentration breeches antioxidant defense you get apoptosis
- Caused by reactive oxygen species
What kind of secondary structure is rich in protein aggregate (the amyloid)?
- Beta rich sheets.
the formation and disintegration of a protein aggregate
Dynamic of protein aggregation
Unfolded protein response is triggered by the stress of which organelle?
Endoplasmic reticulum
MAPs are sequestered into protein aggregates, disrupting their functions
Loss of function mechanism
protein aggregates pose a direct physical obstacle to the axonal transport
Gain of function mechanism
- What are the two main
cytopathological features of Alzheimer’s Disease?
- 1) Accumulation of the β‐amyloid peptide extracellularly within the brain (known as senile/neuritic plaques)
- 2) Hyperphosphorylated and cleaved form of the microtubule‐associated protein tau in the cytosol (known as neurofibrillary tangles, NFT)
- What are the two pathways of APP processing?
-Nonamyloidogenic (α‐secretase) pathway
-Amyloidogenic (β‐secretase) pathway
-generate non‐toxic soluble p3 peptides
* Happens in the cell surface.
* Proteolyzed by α -secretase and y-secretase
Nonamyloidogenic (α‐secretase) pathway
-generate Aβ peptides to form amyloid plaques
* Happens in the endosome (direct or reinternalized)
* Cleaved by β-secretase and then y-secretase cleaves APP C-terminal domain to make different Aβ peptides.
* YENPTY sorting motif couples APP to SorLA/LR11 in the trans‐Golgi network, preventing APP from interacting with β‐secretase, so goes to nonamyloidogenic pathway
Amyloidogenic (β‐secretase) pathway
Which Aβ peptide is the most toxic form?
Aβ42
What is the main catalytic protein component of the γ-secretase complex
Presenilin 1 (PS1) or Presenilin 2 (PS2)
How does Aβ toxicity cause AD pathology and what are these major pathological features?
-Aβ can generate reactive oxidative species
-Aβ can ACTIVATE ENZYMES to control and phosphorylation of tau
-Aβ ASSEMBLIES promote neuroinflammation and excitotoxicity
-Aβ HAS INHERENT HYDROPHOBICITY
Aβ assemblies and tau aggregation together cause _____ _____, loss of synapses and neurons, and activation of glia cells to release neurotoxic mediators
synaptic dysfunction
___ cells produce inflammatory mediators that promote neuroinflammation and excitotoxicity
glial
Mutations in which three genes confer the early-onset AD? Why?
APP, PS1, PS2
APP
APP mutations cluster around the γ‐secretase cleavage site
APP is the precursor protein for Aβ generation
o Presenilin 1 (PS1) and Presenilin 2 (PS2)
Catalytic subunits of the y-secretase
- All mutations increase production of the more toxic Aβ42 relative to Aβ40
-Genetic risk of late-onset AD is conferred by polymorphisms but not mutations (50-70% risk is from polymorphisms of the APOE allele)
-high prevalence but low penetrance
-A polymorphism so a genetic risk factor
properties of Late-onset AD
Penetrance and prevalence of late onset of AD
High prevalence but low penetrance
How do we usually find genes associated with late-onset AD
GWAS
How does ApoE influence AD pathogenesis through its Aβ-dependent roles?
-APP trafficking and Aβ production
-ApoE on Aβ clearance
ApoE4 enhances Aβ production because it cannot carry lipids and increases APP endocytosis.
-APP trafficking and Aβ production
-Aβ binding is E2>E3>E4.
-ApoE is a chaperone and E4 is the worst of Aβ accumulates
-ApoE on Aβ clearance
stimulates GSK-3 that hyper phosphorylates Tau
C-terminal
interacts with the mitochondria and causes mitochondria dysfunction
N-terminal
_____ is lipid binding protein that regulates lipid metabolism and E4 can cause BBB dysfunction, CNS dysfunction and cognitive impairment
ApoE
What is the major cytopathological feature of Tauopathies?
fibrillar tau inclusions (NFTs)
What is the precursor form of NFTs?
Paired helical filaments
What is the tau aggregate called in neurons and glial cells in different tauopathies?
-NFTs in neurons, in Pick’s diseases, they are specifically called Pick’s bodies
-Glial tangles in astrocytes or oligodendrocytes
Which diseases belong to Tauopathies
AD, FTDP‐17, PiD
-Mutation that causes tau to form NFTs easier.
-Mutation that causes tau to become hyperphosphorylated.
-Impaired microtubule binding
-Increased tau expression
-Change of 4R:3R ratio from 1:1
possible pathogenic mechanisms of tau gene mutations
FTDP-17 is caused by what kind of change in the tau isoforms?
-FDPT-17 is caused by tau gene mutations, resulting in 4R isoform being overproduced
What are the major tau kinases
-GSK3 and cdk5 are kinases that cause hyperphosphorylation
which compound can inhibit tau kinases to have therapeutic potential?
-Lithium
the two major pathological mechanisms that contribute to tau-mediated neurodegeneration? How do they cause neurodegeneration?
-Tau‐mediated neurodegeneration is resulted from a loss of normal tau function combined with gains of pathological functions of hyperphosphorylated tau
o 1. Loss of normal tau function: microtubules become instable and compromised axonal transport
o 2. Toxic effects of NFTs:
I. Large NFTs pose a direct physical obstacle to axonal transport, resulting in axon degeneration and neuroinflammation
II. NFTs sequester normal tau or other functionally significant proteins
microtubules become instable and compromised axonal transport
Loss of normal tau function
I. Large fibrillary materials pose a direct physical obstacle to axonal transport, resulting in axon degeneration and neuroinflammation
II. NFTs sequester normal tau or other functionally significant proteins
Toxic effects of NFTs
-a group of neurodegenerative diseases caused by Scrapie prion protein (PrPSc
-PrPSc is the misfolded and aggregated version of the normal cellular prion protein (PrPC)
What are prion diseases
What is the most common human prion disease?
Creutzfeldt–Jakob disease
PrPC is largely ___‐helical in structure
α
PrPSc is composed of predominantly of ___‐ sheets and thus aggregation‐prone due to different folding and 3D structure
β
-PrPC can be misfolded to different conformations of PrPSC
prion strains
What is the most prominent characteristic of PrPC knockout mice? What did we learn from PrPC knockout mice?
PrPC expression is an obligate requirement for prion propagation and prion‐induced neurotoxicity
Different mutations can produce different prion strains (PRNP variants) to cause a spectrum of severity of effect, including different ages of clinical onset (incubation times), penetrance, histopathological lesion profiles, neuronal target areas, and clinical symptoms
- Polymorphisms can also cause some strong modifying effects
genotype-phenotype correlations in inherited human prion diseases
- Which diseases belong to α-Synucleinopathies?
*PD, PDD, DLB, MSA
What are the hallmark cytopathological features of α-Synucleinopathies?
- Lewy bodies
- Lewy neurites
- MSA –> glial cytoplasmic inclusion
How do mutations in α-syn cause α-syn pathology
- Missense mutations reduce its binding to lipid membranes and increase α-syn aggregation
- Duplication or triplication lead overexpression of α-syn and increase its aggregation in α-synucleinopathies
What are the genetic risk factors that may interact with α-synuclein?
*Mutations in β-glucocerebrosidase in lysosomal storage disorder are genetic risk factors that may interact with α-synuclein to cause α-synucleinopathies
What is the hallmark cytopathological feature of multiple system atrophy?
- Glial Cytoplasmic inclusions – α -Synuclein inclusions are mainly found in glial cells
cardinal clinical motor features of PD?
Tremor at rest, Rigidity, Akinesia, Postural instability
Can PD also have other non-motor symptoms?
Other non-motor symptoms are common so yes
PD is mainly caused by loss of which type of neurons in where?
Selective loss of dopaminergic neurons
what are the genes associated with in EOPD
Parkin, DJ1, and PINK1
Parkin is a ____ ligase involved in mitochondrial homeostasis
E3
___-to-___ ascending progression of alpha-syn pathology from brainstem in early stages to limbic and neocortical areas in the later stages
caudal to rostral
- Why SN DA neurons are particularly vulnerable to α-syn pathology?
Because they dependent on mitochondrial energy, use L-type calcium channels so have higher calcium conductance, low levels of calcium-binding proteins so more susceptible to the perturbation of calcium homeostasis, are highly arborized, and use catecholamines (dopaminergic) which are highly reactive
- ATP REQUIRED
- Activation of caspase
cascades - Chromatin condensation
- Nuclear/DNA fragmentation
- Cytoplasmic blebbing to form
the apoptotic bodies
*INTRINSIC PATHWAY
**WITHOUT CAUSING INFLAMMATION
Initiator caspases: Caspase 9
Effector Caspases: Effector Caspase 3, 6, 7
apoptosis
*ATP not required
*INFLAMMATION OCCURS
*EXTRINSIC PATHWAY
Initiator cascades: Caspase 8 and 10; release of cytochrome c
effector capsases: Effector Caspase 3, 6, 7
necrosis
the repeat expansion acts as a sink for RNA‐binding proteins (RBPs) and sequesters the RBPs into RNA foci, disrupting their native functions
Sequestration Hypothesis
____ is the worst of Aβ accumulates
E4
-is a small proteinaceous infectious particle that is resistant to inactivation by most procedures that modify nucleic acids
-is the misfolded and aggregated version of the normal cellular prion protein (PrPC)
causes of prion disease
t/f death stimuli cannot trigger more than one mode of cell death
f, it can
t/f oxidative stress always causes damage?
f
AD when it is localized extracellularly
Aggregate: ABeta
form: senile (neuritic) plaque
AD when it is localized in cytosol
form: neurofibrillary tangle (NFT)
PD protein aggregate
alpha-synuclein
PD form
Lewy bodies
what does prolonged activation of unfolded protein response (UPR)
cell death
dementia with Lewy bodies form what protein aggegrate
alpha-synuclein
HD forms what aggregate
polyglutamine
HD forms what
inclusions
what is the major determinant for the toxicity of a protein aggregate **ON EXAM
the dynamic btw the formation and the disintegration of a protein aggregate
amyotrophic lateral sclerosis protein aggregate
TDP-43
amyotrophic lateral sclerosis form
inclusions
prion disease protein aggregate
PrP^Sc
prion disease form
amyloid plaque
which of the following components belong to the ubiquitin proteasome system **ON EXAM
ubiquitin
26S proteasome
Parkin
what is the underlying mechanism of action for memantine *** ON EXAM
to reduce excitotoxicty
why is penicillin 1 and 2 is important *** ON EXAM
because they are catalytic subunit of gamma-secretase
which of the following gene mutation will NOT cause early onset of AD
ApoE4 – genetic risk factor not mutation
***ON EXAM/QUIZ which of the following statement regarding ApoE in pathogenesis of AD is correct
genetic risk for developing AD: ApoE4>ApoE3>ApoE2
in AD, tau is ____ ____ **on EXAM
wild type
in FTDP-17, tau is ____ **ON EXAM
mutated
Mutations in intron 10 can change the alternative splicing of exon 10 of MAPT (tau gene), resulting in ____ isoform being overproduced **ON EXAM
4R
modification in the pathological tau aggregates *** ON EXAM
hyperphorphorylation
a pt has a single nucleotide mutation in the region indicated by the black arrow inside the (tau gene), resulting in front temporal dementia and Parkinsonism linked to the chromosome 17. what do you think is the underling molecular pathogenesis of the disease? ***ON EXAM
the mutation changed the alternate splicing of axon 10 of MAPTs resulting in the 4R isoform being overproduced
PD only has motor deficieny and nothing else? T/F **ON EXAM
F cause can also have dementia
does necrosis cause inflammation
yes
which of the following statements regarding the autophagy lysosomal pathway is NOT correct
the aytophagy lysosomal pathway is a pathological response and is always toxic to the cell
-NOT ALWAYS TOXIC that is why it is false
what is not true about apoptosis, does it cause inflammation
no
α-synuclein is similar to which pathogenic protein
prion protein (PrPSc)
- Synaptic and trafficking impairments
- Impaired modulation in dopamine release
- impairs mitochondrial function
- Loss of α-Syn function
- α-Syn oligomers are capable of forming pores in membranes: cell toxicity and death due to increased Ca2+ permeability
- α-Syn aggregate can interfere axonal transport and sequester normal α-Syn
*Neurotoxic gain-of-function effect
How does α-syn pathology cause neuronal cell death in sporadic PD and what are the roles of other environmental risk factors in the pathogenesis of sporadic PD?
- inhibition of proteasomal function: Aggregates or generation of misfolded proteins may lead to neuronal cell death
- Environmental interactions include exogenous neurotoxins which are involved in ROS production and disruption of Ca2+ homeostasis
1) Overactivity of indirect pathway
2) Underactivity of direct pathway
3) oversuppression of the thalamus
4) Decreased excitation of motor cortex neurons
5) Resulting in bradykinesia or hypokinesia
major cellular events (Cellular Pathophysiology) during the pathogenesis of PD?
which of the following protein is not formed by tau aggregate
GCI
changing of the tau will cause tauopathies t/f
f
AD (extracellular)
aggregate: Abeta
form: plaque
location: extracellular
AD (cytosolic)
aggregate: tau
form: NFTs
location: cytosolic
HD
aggregate: polyglutamine
forms: inclusions
location: nuclear
PD
aggregate: alpha-syn
forms: Lewy bodies
location: cytosolic
prion disease
aggregate: PrPsc
form: amyloid plaques
location: extracellular
