exam 2 study guide Flashcards
- What is the cause of trinucleotide repeat diseases?
expansions of pre-existing unstable tandem repeat sequences
The expansions of unstable repeats are caused by what reason and occur within which regions of the genes?
caused by the slippage of DNA polymerase during DNA replication or repair
-This is within the CAG DNA sequence
what are the three pathogenic mechanisms underlying trinucleotide repeat diseases?
- loss of function of protein
- gain of function of RNA
- gain of function of protein (expansion of CAG-repeat)
what are the important features of trinucleotide repeat disease
-inherited
-intergenerational repeat instability
-anticipation
-variability in expressivity or severity of the disease
-selective vulnerability
the offspring with the further-expanded repeat have an earlier onset and more severe disease course than did the parent
anticipation
repeat length rarely causing a disease but that is likely to expand to disease-causing mutation length in successive generations
premutation
Mutation in which gene causes Fragile X Syndrome?
FMR1
what happens when there is the protein (frataxin) function
causes iron accumulation in the mitochondria
What is the pathogenic mechanism of Friedreich Ataxia?
loss of protein (frataxin) function -> iron accumulation in the mitochondria
What is the pathogenic mechanism of spinobulbar muscular atrophy?
caused by expansion of a CAG repeat in the coding region of the androgen receptor
why does spinobulbar muscular atrophy mainly affect males
females usually do not have enough androgens to bring mutated androgen receptors to the nucleus to mediate their pathogenic effects
What is the pathogenic mechanism of mutant Ataxin-1 in Spinocerebellar Ataxias 1?
Gain of protein function in Ataxin 1 causes SCA1
Mutant Ataxin‐1 then contributes to SCA1 pathogenesis through disturbing the transcriptional corepressors/ coactivators pathway
- Huntingtin is a _____ ______protein to mediate protein-protein interaction and is involved in many pathway
multifunctional scaffold
Mutant Huntingtin alters the protein interacting with different proteins, thereby disrupting many _____ functions
cellular
Fragile X Syndrome loss of protein function, gain of RNA function, gain of protein function?
loss of protein function
Myotonic Dystrophy I & II loss of protein function, gain of RNA function, gain of protein function?
gain of RNA function
Fragile X–Associated Tremor Ataxia
Gain of function of toxic RNA
Friedreich Ataxia
Loss of protein function
Spinobulbar Muscular Atrophy (polyQ disease)
Gain of function of toxic protein
Spinocerebellar Ataxia 1 (polyQ) disease)
gain of function of toxic protein
Huntington’s Disease (polyQ disease)
Gain of function of toxic protein
TDP43 (ALS) gain of function, loss of function, or both?
both
gain of function (cytoplasmic aggregation) and loss of function (abnormal RNA processing)
1.loss of protein (DPR) function;
(2) gain of function of the toxic RNA;
(3) gain of function of toxic protein (DPR protein accumulation)
C9ORF72
SOD1 (ALS) mechanism
gain of toxic function
- ALS patients not only have motor symptoms but usually FTLD symptoms too during disease progression.
- FTLD patients also have ALS symptoms.
- ALS and FTLD have the same pathological protein inclusions: TDP 43 & FUS
- Inherited ALS and FTLD patients have the same genetic cause: chromosome 9 open reading frame 72 mutation
Why amyotrophic lateral sclerosis and frontotemporal lobe degeneration viewed as the same disease?
types of neurons affected in ALS
UMNs, LMNs, Frontal cortex neurons, temporal neurons
Which type of neurons are least vulnerable in ALS
Sensory, autonomic and cerebellar neurons are mostly spared
What are the three different histopathological inclusions in ALS?
Bunina bodies
skein-like inclusions (TDP-43)
basophilic inclusion (FUS inclusion)
-protein aggregation
-alterations in RNA metabolism
-oxidative stress
-mitochondria dysfunction
-impaired axonal transport
–impaired protein degradation
**Glial cells are also involved
pathological mechanism is ALS
SOD1 is involved in _____ ____ ____(prevents oxidative damage)
free radical scavenging
-Mutant SOD1 misfolds and has toxic effects on the cell’s protein degradation machinery, impairing both the ubiquitin-proteasome and autophagy pathway
Wild‐type SOD1 is aggregation‐prone: in sporadic ALS, oxidized wild type SOD can misfold and is toxic to motor neurons t/f
t
How do UBQLN2 and Valosin-containing proteins (VCP) get involved in ALS pathogenesis?
contains proteins that impair protein degradation machinery
What are the pathogenic mechanisms caused by repeat expansion in the C9ORF72 gene in ALS?
loss of protein mRNA levels get reduced by 50% (may be _____ causing loss of function effect)
haploinsufficency
What are the pathogenic mechanisms caused by repeat expansion in the C9ORF72 gene in ALS?
gain of toxic RNA function
loss of protein function –> haploinsuffuciency
gain of protein function
- The common:
- Both TDP43 and FUS are RNA-binding proteins
- Both TDP43 and FUS bind to very long intron sequences
- Both TDP43 and FUS have the prion-like domain renders the aggregation propensity
- Both TDP43 and FUS shuttle between nucleus and cytoplasm
common btw TDP-43 FUS
t/f - TDP43 and FUS co-aggregates in the same protein inclusion
false, it doesn’t
What are the two clinical disease course of most MS?
RRMS and SPMS
caused by focal areas of inflammatory demyelination followed by resolution of the inflammation and edema and remyelination
Relapsing-remitting MS (RRMS)
after one to two decades, RRMS patients enter a second disease phase characterized by a continuous irreversible neurological disability
Secondary progressive state of MS (SPMS)
what is the major MS-associated gene that influences MS disease susceptibility?
HLADRB1 gene (The only consistent MS‐associated gene)
What is the major reason for irreversible neurological functional decline in MS patients in the SPMS phase?
axonal degeneration NOT inflammatory demyelination
both white and gray matter
type 1
extensive gray matter
type 3
cortical lesions have intact blood brain barrier and almost no inflammation
gray matter
microglia
gray matter
cytotoxic t cell and macrophage
white matter
axonal degeneration continue in environment other than the inflammatory demyelination lesion
chronic demyelination lesions
Degeneration of chronically demyelinated axons is caused by imbalance between energy supply and demand
Limited energy supply due to ischemic
Chronically demyelinated axons increase the energy demand to restore nerve conduction, resulting in axoplasmic ATP production decreases and increases axoplasmic Ca2+
Loss of trophic support from oligodendrocytes
mechanisms underlying the degeneration of chronically demyelinated axons
what are the major causes of primary demyelination in CNS
- Genetic mutation or abnormality
- Inflammatory damage to myelin and oligodendrocytes
- Oligodendroglial loss due to secondary damage from ischemia or infection
ischemia or infection causes _____
Periventricular leukomalacia
mutation of ____ causes of Pelizaeus–Merzbacher disease
PLP1
- Myelination
- Organizing the axonal cytoskeleton for maintenance of axonal integrity
- Trophic support for axons
- Participation in signaling networks with neurons
functions of oligodendrocytes
In developmental myelination, _____ diameter axons are enwrapped with proportionally ____ myelin
larger; thicker
in remyelination, the myelin sheath length and thickness remain roughly constant ______/_____regardless of the axon diameter
THINNER/SHORTER
t/f G ratio is decreased in remyelination
f, it increases
*Persistent activation of notch signaling during OPC differentiation
*Persistent activation of WNT signaling during OPC differentiation
*Failure of expression of YY1 transcription factor
*Impairment of HDAC recruitment during OPC differentiation
*No acute inflammation
*A sustained demyelinating insult
*Poor clearance of myelin debris
*Block axon derived signals during OPC differentiation
conditions that could cause remyelination failure
axon degeneration that is morphologically similar to that occurring after injury
wallerian degeneration
o _____ and ______ of the initial lesion is well defined
o Distal portions of injured axons fragment after _______ latent phase, lasting 36-44 hours in the mouse sciatic nerve
pathological features of wallerian degeneration
location; timing
predictable
mutant protein will bring NMNAT1 and bring it to the cytoplasm
slow wallerian degeneration protein
WLDS Delays Wallerian degeneration up to tenfold when ______ within axons
overexpressed
- Overexpression of WLDS (slow Wallerian degeneration protein)
- Overexpression of NMNAT2
- Disruption of palmitoylation of NMNAT2
- Deletion of SARM1
- Deletion of PHR1 (PAM‐Highwire‐Rpm‐1)
- Decrease intra‐axonal calcium concentration
kinds of manipulations or conditions can delay Wallerian degeneration
axon degeneration that is morphologically similar to that occurring after injury but may not be induced by traumatic injury
Wallerian-like degeneration
Is axon degeneration in different neurodegenerative diseases all mediated by Wallerian-like mechanisms?
no
cell body response to CNS and PNS injury
Chromatolysis
the cut axonal end transforms into a ____ ____ -LIKE STRUCTURE
PNS response of axons to injury
growth cone
what is the axon response to CNS injury
forms an end blub or retraction bulb
what ish the PNS response to injury in non neuronal cells
clearance of axon and myelin debris by macrophages
proliferation and hypertrophy of all 3 types of glial cells (astrocytes, microglia, and oligodendrocytes)
reactive gliosis (non neuronal cells response to CNS injury)
upregulate expression of chondroitin sulfate proteoglycans and for glial scar
Reactive astrocytes
(non neuronal cells response to CNS injury)
: 1st injury at the peripheral branch increases the regenerative responses to the second lesion
conditioning lesions
- Neuropoietic cytokines
- Cyclic AMP (cAMP) increase
- Increase axonal transport
- Increase local protein synthesis
- Silencing of electrical activity
five mediators that play a role in the effect of a conditioning lesion on axon regeneration
- Provide trophic factors and cytokines or re‐activate trophic responses
- Downregulate suppressor of cytokine signaling 3 (SOCS3) by increasing cAMP levels to promote inflammatory cytokine‐ induced activation of axon regeneration
- Activate GSK3 to regulate microtubule dynamics for growth cone formation
- Eliminating PTEN to activate mTOR kinase to increase protein synthesis for axon regeneration
- PTEN↓, SOCS3↓
- cAMP↑, cytokine↑, mTOR↑, GSK3↑ neurotrophic factors ↑
functions to promote axon regeneration
NMNAT2 is found in the ____ and ____- and is abundant in the brain
cytoplasm + axoplasm
NMNAT1 is stably localized to the ____ and widely expressed
nucleus
WLDS is predominantly nuclear but small amounts of WLDS are also present in axons and this is the location (the _______) where WLDS acts to delay injury‐induced degeneration
axoplasm
***which of the following events does not occur in the replacing remitting phase of MS
irreversible neurological disability and dysfunction
***which of the following statements regarding MS is NOT correct
the irreversible neurological decline int he secondary progressive state of MS if mainly cause by inflammatory demyelination
t/f RNA from both mutant alleles are transcribed and spliced normally but are retained in foci within the nucleus and ARE TRANSLATED INTO PROTEINS
F, it is not translated into proteins
t/f FMR1 mRNA is not translated to protein and CGG repeat‐containing transcripts
t
Binding of androgen to the polyglutamine‐expanded AR and the subsequent translocation of mutated AR to the nucleus are NOT required for onset of disease t/f
FALSE, IT IS REQUIRED
both fragile X syndrome and fragile x-associated tremor ataxia syndrome (FXTAS) are caused by a repeat expansion in the same gene, the FMR1, but they show different clinical symptoms, why? ***ON EXAM
b/c FMRI transcripts are not translated in FXTAS, resulting in the RNA gain of function based pathogenic mechanism and DRAXA us caused by a different loss of protein function based mechanism
why does spinobulbar muscular atrophy mainly affect males **ON EXAM
females do not have enough androgens to bring mutated androgen receptors to the nucleus to mediate their pathogenic functions
Huntington’s disease is a _____ movement disorder
hyperkinetic
In HD, medium spiny neurons that project to the ____ ____external degenerate
globus pallidus
Huntingtin uses HEAT repeats to mediate protein‐protein interactions and is a
______ ____ protein **ON EXAM
multifunctional scaffold protein
t/f normal and mutated huntingtin interact differently with numerous other proteins
t
Amyotrophic lateral sclerosis is NOT a polyglutamine disease t/f
t
*** ON EXAM
which disease affects what type of neuron in ALS, PLS, PMA, SMA
ALS– both upper and lower
PLS – upper motor neurons
PMA – lower motor neurons
SMA – lower motor neuron and is INHERITED
ALS and FTLD are the same disease with same or different clinical spectrums
different
which of the following neuronal types is involved in amyotrophic lateral sclerosis **ON EXAM
UMN, LMN, Frontal cortical neurons, temporal cortical neurons
WHICH MOTOR NEURON IS MOST VULNERABLE
FF motor neuron
WHICH MOTOR NEURON IS LESS VULNERABLE
FFR motor neuron
____ ____ motor neurons are most resistant in ALS
slow tonic motor neurons are most resistant in ALS
*** ON EXAM Which of the following statements referring ALS is not correct
glial cells are not involved in the pathogens of ALS
*** ON EXAM which of the following statements regarding the pathogenic proteins in ALS is not correct
n ALS, only mutant superoxide dismutase 1 (SOD1) becomes misfiled and wild type SOD1 does not misfold
t/f TDP43 always need to be mutated to cause ALS
f
t/f Both TDP43 deficiency and TDP43 (wild‐type and mutant) overexpression are hazardous to the cell
t
t/f MS is inherited
FALSE NOT INHERITED
what is the following statements regarding MS is not correct ** ON EXAM
the irreversible neurological decline in the secondary progressive state of MS is mainly caused by inflammatory demyelination
which of the following events does not occur in the relapsing remitting phase of MS ***ON EXAM
irreversible neurological disability and dysfunction
***differentiation failure represents a major cause of remyelination failure (failure happens mostly in the_____ stage)
differentiation
t/f remyelination depends as much on the precise timing of action as on the presence or absence of certain factors
t
___ is the most important factor for remyelination failure
age
***is there reactive gliosis in PNS and generates glial scar
FALSE
Expansion of the _____ repeat in 5’-UTR of FMR1 gene causes Fragile X Syndrome.
CAG
-loss of FMRP protein,
-maximum translation of FMRP target mRNAs,
-exaggerated mGluR-dependent long-term depression (LTD),
–>resulting in abnormal synapse development and immature synapse
pathogenic processes of fragile X syndrome
15% of MS patients, with rare or no relapses
Primary progressive MS (PPMS)
_____ matter has immune mediated inflammation
white
