exam 1 Flashcards
diseases involved the progressive loss of structures or functions of neurons
neurogenerative diseases
necrosis, apoptosis, autophagic cell death and excitotoxicity
neuronal cell death
excessive of O2 free radicals that breach oxidant defense with consequent detriment
-cause reactive O2 species
oxidative stress
-repeat extension cause pre-mRNA not properly translated and accumulate to form RNA foci, disrupting functions of RNA binding proteins
RNA mediated toxicity
altered protein synthesis, post translational modification, abnormal cleavage, mutation, misfolded protein
Protein aggregation (ER stress/ unfolded protein response)
malfunction or overload of UPS/ defective autophagy
protein degradation (the ubiquitin-proteasome system and autophagy)
protein aggregates pose a direct physical obstacle to the axonal transport and sequester microtubule - associated proteins)
impaired axonal transports
what mechanism are shared in neurodegenerative disease (6)
-neuronal cell death
-oxidative stress
-RNA mediated toxciticty
-protein aggregation
-protein degradation
-impaired axonal transports
toxicity caused by excessive stimulation of the glutamate receptors
excitotoxicity
-not a program cell death
-loss of ATP
-cause inflammation
necrosis
-extrinsic (receptor mediated)
-intrinsic (mitochondria mediated) pathway
*MAINTENANCE OF ATP, activation of caspase cascades, chromatin condensation, nuclear fragmentation –> apoptotic bodies
**WITHOUT CAUSING INFLAMMATION
apoptosis
-Loss of ATP
-Loss of ion gradients
- Loss of mitochondrial membrane potential
-Cell and organelle
-swelling
-Cell lysis
*inflammation
necrosis
-Maintenance of ATP
* Activation of caspase
cascades
* Chromatin condensation
* Nuclear/DNA fragmentation
* Cytoplasmic blebbing to form
the apoptotic bodies
*ATP required
-extrinsic and intrinsic apoptosis
Apoptosis
- stress to mitochondria
- release of cytochrome c
- initiator caspase 9
- effector caspase 3
intrinsic pathway of apoptosis
- death ligands binds to death receptors
- initiator caspase 8 or 10
- effector caspase 3
extrinsic pathway of apoptosis
-program cell death involved autophagy lysosomal pathway (ALP)
-autophagic vacuoles
-plays a pro-survival role
autophagic cell death
t/f death stimuli cannot trigger more than one mode of cell death
f, it can
repeat expansion acts as a sink for RNA binding proteins and sequesters the RBPs into RNA foci, disrupting their native functions
sequestering hypothesis
t/f oxidative stress always causes damage?
false
-lose their native structure and form fibrils (amyloid fibrils) – highly ordered stacks of B sheet rich fibrils
protein aggregation
what are the causes of protein aggregation
- cellular stress
- mutations
- overproduction of proteins
- abnormal post translational modifications or proteolysis
- impaired folding machinery or proteasome
which of the secondary structure are most common in protein aggregate **ON EXAM
b sheet
AD when it is localized extracellularly
Aggregate: ABeta
form: senile (neuritic) plaque
AD when it is localized in cytosol
Aggregate: Tau
form: neurofibrillary tangle (NFT)
PD protein aggregate
alpha-synuclein
PF form
Lewy bodies
the formation and the disintegration of a protein aggregate
dynamic of the protein aggregation
the unfolded protein response **ON EXAM
endoplasmic reticulum stress
what does prolonged activation of unfolded protein response (UPR)
cell death
____ determine toxicity
dynamic
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
is a small basic protein tagged to target proteins (normal protein
turnover or misfolded protein) destined to be degraded by the 26S proteasome
ubiquitin
-degrade organelles or large protein aggregates
*promotes cell survival through provision of molecular building blocks
*inadequate or defective autophagy promotes cell death
autophagy-lysosomal pathway (ALP)
-mutations in E3 ligases
PARKIN IN PD
axonal components synthesized in the cell body are packaged into vesicles and translocated from the cell body into the axonal processes and toward the synapses
anterograde axonal transports
recycled proteins, organelles, and signaling complexes are transported from the terminal of axon toward the cell body
retrograde axonal transport
Two mechanisms of impaired axonal transports cause neurodegeneration
- Loss of function mechanism: MAPs are sequestered into protein
aggregates, disrupting their functions - Gain of function mechanism: protein aggregates pose a direct physical obstacle to the axonal transport
which of the following components belong to the ubiquitin proteasome system **ON EXAM
- ubiquitin
- 26S proteasome
- Parkin
the most important genetic risk factor, with semidominant inheritance, for LOAD (late‐onset AD)
ApoE
precursor protein of ABeta peptides
APP (amyloid precursor protein)
-progressive loss of short term memory
AD
AD is neurologically characterized by
- accumulation of the beta-amyloid peptide (senile/neuritic plaques)
- hyperphosphorylated and cleaved for of tau (neurofibrillary tangles, NFT)
increase production, decreased degradation/ reduced clearance
accumulation of Abeta
impairs ABeta clearance and promotes Abeta deposition; truncated E4 is neurotoxic
ApoE4
hyperphosphorylated and mis-localized to neuronal soma and dendrites and forms NFTs
Tau
treatment of AD
- cholinesterase inhibitors
- memantine: glutamate-gated NMDA receptor antagonist to reduce excitotoxicity
- Abeta immunization –> aducanumab by biogenesis
glutamate-gated NMDA receptor antagonist to reduce excitotoxicity
memantine
wha tis the underlying mechanism of action for memantine *** ON EXAM
to reduce excitotoxicty
Abeta is generated from ____ ____ ____ by proteolytic cleavage
amyloid precursor protein
The C‐terminus of APP contains a _____ sorting motif, which brings APP to the trans‐Golgi network, preventing APP from interacting with β‐secretase
YENPTY
generate non‐toxic soluble p3 peptides
Nonamyloidogenic (α‐secretase) pathway
generate Aβ peptides to form amyloid plaques
Amyloidogenic (β‐secretase) pathway
Nonamyloidogenic pathway happens
in the ____ ____
cell surface
APP is proteolyzed by ___‐secretase and
then ______-secretase (nonamyloid pathway)
α‐secretase; γ‐secretase
Amyloidogenic pathway occurs in the ____
endosome
APP is sequentially cleaved by __‐secretase
(BACE1) followed by ___‐secretase to generate *ABeta peptide (amyloidogenic)
B, gamma
is the most amyloidogenic (toxic) form
Aβ42
why is penicillin 1 and 2 is important *** ON EXAM
because they are catalytic subunit of gamma-secretase
Mutations in the presenilin 1 or 2 (PS1 or PS2) gene cause early‐onset ___
AD
the composition of the membrane such as cholesterol content or the dimerization of APP can modulate what 2 secretase
beta and gamma
has inherent hydrophobicity
Abeta
Aβ is removed from brain by ____ ____ ____
perivascular lymphatic drainage (or across blood brain barrier)
ABeta in AD pathogenesis
- reactive oxidative species
- cleavage and phosphorylation of tau
- synaptic loss and dysfunction
- neuroinflammation and excitotoxicity
what is the potential treatment based on the ABeta pathway in AD
blocking the internalization of APP into the ENDOSOME
early onset is usually caused by?
autosomal dominant mutations, full penetrance
sporadic AD is half risk is conferred by the APOE allele) conferred by common
_____, low penetrance but high prevalence
polymorphisms
mutations in ___ ___ ___ gene cause early onset AD
APP, presenilin 1 or 2 (PS1 or PS2)
_____ allele increases AD risk
ApoE4
Novel LOAD genes are usually identified by
genome‐wide association study (GWAS)
which of the following gene mutation will not cause early onset of AD
ApoE4 – genetic risk factor not mutation
ApoE gene encodes three protein isoforms (ApoE2 ,E3 and E4) due to ____
polymorphisms
how many form of ApoE are there?
Three informs, ApoE2, E3, E4 differ at a.a. residues 112 and 158, which have a major impact on APOE structure and function
interaction btw N & C domain: cleavage ___ (increase/decrease) and Abeta binding ____ (increase/decrease)
increase; decrease
____ modulate APP trafficking and Aβ production
ApoERs
_____is an Aβ chaperone (Aβ binding: E2>E3»E4)
ApoE
___‐terminal‐truncated form of ApoE4 is neurotoxic and stimulates tau phosphorylation (form pre‐NFTs)
C
__‐terminal fragment is neurotoxic
N
ApoE4 ___‐terminal fragment (1‐272) can bind to subunits of mitochondrial respiratory complexes and perturb their activities
N
___- terminal fragment will bind to the mitochondria that will cause mitochondrial dysfunction
N
what increases risk of LOAD
E4
___ has a protective effect against AD
ApoE2
***ON EXAM/QUIZ which of the following statement regarding ApoE in pathogenesis of AD is correct
genetic risk for developing AD: ApoE4>ApoE3>ApoE2
which of the following statements regrind necrosis is not correct ** on QUIZ
necrosis does not cause inflammation
which of the following statement regrinding the autophagy-lysosomal pathway is not correct **ON QUIZ
the authophagy lysosomal pathway is a pathological response an is always toxic to the cell
Where is Abeta generated **on quiz
endosome
late onset of AD is identified by what **on quiz
GWAS
-NFTs
-Paired helical filaments
-hyperphosphorylated tau
tauopathies
____ which contain the pleated beta sheet structure, is the precursor form of NFTs and can self assemble to form ____
PHF; NFTs
what are some tauopathies ** ON EXAM
AD, frontotemporal dementia, Parkinsonism linked to chromosome 17, Pick’s disease
microtubule‐associated protein (MAP) that stabilizes microtubules and promotes microtubule assembly
tau
involved in maintenance of neuron and axon morphology, and involved in anterograde/retrograde axonal transport
tau
In normal adult brain, _R and _R isoforms are expressed in a 1:1 ratio; deviations from this ratio can cause tauopathies (e.g. in FTDP‐17, 4R>3R)
3;4
-N‐terminal projection domain
-a repeat of microtubule binding motif in c terminal
insertions in the is-forms
binding ability of tau is post‐translationally regulated by serine/threonine phosphorylation
the microtubule
In normal physiological conditions, ___ is in constant dynamic equilibrium, on and off the microtubules (MTs)
tau
ON the MT
dephosphorylation
OFF the Mts
phosphorylation
- autosomal dominant mutations in tau
- prove that tau dysfunction is sufficient to cause neurodegeneration and dementia (different to AD)
- NFTs and Glial tangles
- change the ration of 3 and 5 repeat tau is-forms, resulting int eh overproduction of 4 repeat tau
Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP‐17)
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
kinases involved in tau
GSK3, cdk5
is the most commonly seen abnormal posttranslational
modification in the pathological tau aggregates *** ON EXAM
hyperphorphorylation
____ can inhibit GSK3 to reduce tau phosphorylation
lithium
Pick’s disease (PiD) is frontotemporal dementia with ____‐repeat aggregated tau proteins only inneurons (called Pick bodies)
3
FTDP‐17 has ___‐repeat tau in
neurons and glia
4
tau becomes requested into ____ in neurons and ____ ____ in astrocytes and oligodendrocytes
NFTs; glial tangles
Tau mediated neurogeneration results from what two things?
- loss of normal tau function
- gains of pathological functions of hyperphorphorylated tau
microtubules become instable and compromised axonal transport
loss of normal tau function
what are the toxic effects of NFTs
-pose directly physical obstacle to the axonal transport
-NFTs sequested normal tau or other functionally significant proteins
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
a group of neurodegenerative diseases caused by Scrapie prion protein (PrPSc)
prion disease
the most common human prion disease
Creutzfeldt–Jakob disease
infectious agent of prion diseases
-misfolded and aggregated version of the normal cellular prion protein (PrPc)
scrapie prion protein
PrPC is largely __‐helical in structure while PrPSc is composed of predominantly of __‐ sheets and thus aggregation‐prone
α; β
PrPC can be misfolded to different conformations of PrPSC
prion strains
prion protein gene in humans
PRNP
PrPC knockout mice are completely resistant to prion disease when inoculated with prions, indicating that PrPC expression is an obligate requirement for prion ____ and ___-____ ____
propagation; prion‐induced neurotoxicity
In various age‐related neurodegenerative diseases, different disease‐related proteins share biochemical and biological features that are reminiscent of prions and their proteinopathies are transmitted in a prion‐like fashion
Prion‐like hypothesis
(PMCA)
Protein Misfolding Cyclic Amplification (PMCA)
- Is a simple, fast and efficient technique to amplify the disease‐ associated, infectious form of the prion protein (PrPSc) or other pathological protein aggregates in vitro
- Can be used to study the strain of the pathological protein aggregate
α‐synuclein inclusions found in the cell bodies and processes of surviving neurons are called ____ ___ and _____ ______
Lewy bodies and Lewy neurites
α‐synuclein inclusions found in the cytoplasm of oligodendrocytes in multiple system atrophy (MSA) are called
glial cytoplasmic inclusion (GCI)
α‐Synucleinopathies include what two diseases / disorders
PD & multiple system atrophy (MSA)
are the major components of α‐synuclein pathological inclusions
NAC domains
Mutations ___ α‐synuclein aggregation or ____ its binding to lipid membranes
increase; reduce
mutations in ____ (E3 ligase for mitochondrial quality control) interact with α‐synuclein
Parkin
The evidence of neuron‐to‐neuron transmission of α‐syn suggests that it has similar properties to
(PrPSc)
Non‐prion neurodegenerative disease proteins (Aβ, tau, α‐syn) are distinct to prions as there is no transmission between individuals
t/f
t
PD only has motor deficieny and nothing else? T/F **ON EXAM
F cause can also have dementia
