exam 2 Flashcards
neurodegenerative disorders show symptoms of impaired balance or uncoordinated movement
ataxia
Most common inherited ataxia
-progressive gait ataxia
Friedreich Ataxia (FRDA)
Autosomal recessive disorder caused by expansion of an unstable GAA repeat in the first intron of the FRDA gene, which encodes _____
frataxin
GAA expansion causes inhibition of transcriptional elongation,
resulting in (increase or decrease) frataxin levels
decrease
-iron‐binding protein and localizes to the inner mitochondrial membrane
-important in mitochondrial iron storage and regulation of iron levels
frataxin
- Accumulation of iron in the mitochondria and impair biosynthesis of Fe‐S cluster‐
containing enzymes - Decreased cellular energy production
- Increased free radical production, and increased sensitivity to oxidative stress
loss of frataxin causes
what are the potential therapeutics for frataxin
- antioxidant
- histone deacetylase inhibitor to increase frataxin levels
- agents to decrease iron accumulation
Autosomal dominantly inherited disorder
* _____ is the most common form of adult muscular dystrophy
Myotonic dystrophy type I (DM1)
Symptoms for both DM1 and DM2 include _____ ____
muscle degeneration
caused by expansion of a noncoding CTG repeat in the 3’‐UTR of DMPK (kinase)
DM1
caused by expansion of a CCTG repeat in intron 1 of ZNF9 (transcription factor)
DM2
is there functional similarity btw DMPK and ZFN9
no
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
The expanded CUG/CCUG repeats in untranslated regions cause ______ of alternative splicing of certain RNAs (gain of toxic function of the RNA)
misregulation
Expanded CUG and CCUG repeats affect RNA splicing in a ____ fashion: DMPK and
ZFN9 RNAs are processed normally but splicing of other RNAs is affected
trans
Toxic RNAs affect functions of two splicing factors, _____ and ____
CUG‐BP1 and MBNL
FXTAS is cause by _____ _____ of FMR1 gene
permutation allele
Symptoms: late‐onset ataxia
-caused by an RNA gain‐of‐function‐based mechanism by altering the function of RNA‐binding protein (different to loss of protein function mechanism in Fragile X Syndrome)
t/f FMR1 mRNA is not translated to protein and CGG repeat‐containing transcripts
t
encoding the protein FMRP
Mutations in FMR1
Mutation causes an expansion of an unstable noncoding CGG repeat in the 5’‐UTR of _____
FMR1
repeat length rarely causing a disease but that is likely to expand to disease‐causing mutation length in successive generations
Premutation
expansion of a CAG repeat in the coding region of the _____ receptor
(AR) gene (a polyglutamine disorder; protein gain‐of‐function‐based mechanism)
androgen
AR is a transcription factor belonging to the ___ receptor superfamily
nuclear
Spinobulbar Muscular Atrophy __- linked recessive disorder
x
Mutation causes gain‐of‐function mutant androgen receptor (AR) and ____ ____ is androgen dependent in spinobulbar muscular atrophy
**Mostly affects males
mutant phenotype
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
Ligand‐induced nuclear translocation of mutant AR but not the transactivation activity of AR is a crucial for ____ pathogenesis
SBMA
both fragile X syndrome and fragile x-associated tremor ataxia syndrome (FXTAS) are caused by a repeat expansion in the same gene, the FMR2, 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
-This family of diseases is caused by expansions of pre‐existing unstable tandem repeat sequences within the affected gene
- occur within either coding or non‐coding regions of the genes
-The expansions of unstable repeats is caused by the slippage of the DNA polymerase
during DNA replication or DNA repair
Trinucleotide Repeat Diseases
Repeat mutations cause three pathogenic mechanism:
(1) loss of function of the protein,
(2) gain of function of the RNA or
(3) gain of function of protein (expansion of a CAG‐ repeat causing Polyglutamine disorders: Huntington Disease/Spinocerebellar Ataxia)
- inherited
- dynamic mutations (intergenerational repeat instability)
- anticipation
- variability in expressivity or severity
- selective vulnerability of certain neurons but consistency target motor system
Features of the trinucleotide repeat diseases
instability of the
repeat length sudden expansion of the length of the tandem repeat in one generation
Dynamic mutations (intergenerational repeat instability)
the offspring with the further‐expanded repeat have an
earlier onset and more severe disease course than did the parent
Anticipation
Thelargertheexpansion,theearliertheonsetandthemoreseverethe
course (the repeat length is inversely correlated with disease onset)
Variability in expressivity or severity of the disease phenotype
_____ disorders caused by a gain‐of‐function mechanism [The repeat unit is (CAG)n in all these disorders]
Polyglutamine
-Mental retardation segregated as an X‐linked trait
Symptoms: moderate‐to‐severe mental retardation
Fragile X Syndrome (FRAXA)
neuropathology of Fragile X Syndrome (FRAXA)
- Dendritic abnormalities
- Abnormal spine shapes and number in the cortex
- Increase of immature long spines
____ repeat expansion on fragile site in fragile X chromosome
CGG
Repeat expansion in fragile X syndrome causes aberrant ______ of CpG island in the 5’‐UTR resulting in decreased histone acetylation and loss of FMR1 expression and FMRP function
hypermethylation
-FMRP is a RNA‐binding protein
-FMRP associates with polyribosomes to control local protein synthesis by
suppressing the translation of mRNAs it binds
Fragile X Syndrome ‐mutation and gene product
- FMRP plays a crucial role in regulating mRNA translation at the synapse
- FMRP binds to mRNA targets and most of these targets are involved in
synaptic function and development
-FMRP suppress translation
FMRP functions
FMRP mutant mice have selective enhancement of _____ dependent long‐term depression (LTD), causing abnormal synapse development and function
(mGluR)
FMRP –> FMRP loses expression in fragile x syndrome –> mRNAs of proteins require LTD –> uncontrolled tralation of mRNA for LTD –> LTD–> ___ ____development, causing immature synapses and synaptic dysfunction
abnormal synapse
AMPAR internalization and mGluR‐LTD are exaggerated, resulting in long immature spines and synaptic dysfunction
No FMRP results in maximum expression of LTD proteins:
demethylating agents
mGLUR antagonists
Fragile X Syndrome ‐potential therapeutics
-mild mental retardation
-Expansion of a CCG repeat in the 5’‐UTR of FMR2
-causing loss of protein function
Fragile XE Syndrome (FRAXE)
Common symptoms for all SCAs and DRPLA
ataxia, tremor, and dysarthria
Common pathologies: cerebellar atrophy in all SCAs and DRPLA, ______ _____ ____
Purkinje cell loss
Expansions of a translated CAG repeat in Ataxin‐1 cause SCA ___
– all autosomal dominant disorders (all polyglutamine disorders)
1
SCA1 is caused by____ ___ ____ _____ mutation in Ataxin‐1 protein (ATXN1)
gain‐of‐protein‐function
Mutant Ataxin‐1 contributes to SCA1 pathogenesis through perturbation
of the transcriptional _____/______ pathway
corepressors/coactivators
-autosomal dominantly inherited disorder
- inverse relationship between age of onset
and repeat length
-Symptoms: _____ (jerky involuntary movements)
chorea in HD
Atrophy of the caudate and putamen (striatum) causes loss of indirect output pathway in ____ ____ in HD
basal ganglia
Huntington’s disease is a _____ movement disorder
hyperkinetic
In HD, medium spiny neurons that project to the ____ ____external degenerate
globus pallidus
Loss of inhibitory input from caudate/putamen → abnormally acvaon of globus pallidus external → diminished excitatory subthalamic output to globus pallidus internal → less tonic inhibion of thalamus → increased excitaon of motor cortex neurons → undesired _____ (“dancelike”) movement in HD
choreiform
HD is caused by expansion of a translated ___ repeat encoded _____ (also a polyglutamine disorder)
CAG; huntingtin
______ is most often seen in Huntington’s Disease ― Paternal inheritance is associated with increased likelihood of repeat‐
length expansion, leading to earlier onset and more severe disease course in the next generation
Anticipation
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
gene: FMR1/FMRP
Gene function: mitochondrial iron binding protein
pathogenic mechanism: loss of protein function
inherited mode: autosomal recessive
pathology: Impair biosynthesis of Fe‐S cluster‐containing enzymes, decreased energy production, oxidative stress
clinical features: ataxia
Friedreich Ataxia
gene: Frataxin
Gene function: RNA binding protein for ↓translation
pathogenic mechanism: loss of protein function
inherited mode: X linked
pathology: exaggerated LTD causes abnormal synapse development
clinical features: mental retardation
fragile X syndrome
gene: DMPK &ZNF9
Gene function: mRNA never translated to proteins
pathogenic mechanism: gain function of toxic RNA
inherited mode: autosomal dominant
pathology: Changed activity of splicing factors cause misregulation of alternative splicing of target mRNAs
clinical features: Muscle degeneration & multisystem disorders
Myotonic Dystrophy I & II
gene: FMR1
Gene function: mRNA never translated to proteins
pathogenic mechanism: gain function of toxic RNA
inherited mode: x-linked
pathology: Altering the function of RNA‐ binding protein (splicing factor)
clinical features: late‐onset ataxia
Fragile X– Associated Tremor Ataxia
gene: Androgen
receptor
Gene function: nuclear
receptor transcription factor
pathogenic mechanism: gain function of toxic protein
inherited mode: x-linked
pathology: Mutant ARs translocated to nucleus and cause toxicity
clinical features: Only affect males (phenotype is androgen dependent); muscle cramps; hypogonadism
Spinobulbar Muscular Atrophy
(polyQ)
disease)
Amyotrophic lateral sclerosis is NOT a polyglutamine disease t/f
t
gene: Ataxin‐1
Gene function: transcription
repressor
pathogenic mechanism: gain function of toxic protein
pathology: Perturbation of the transcriptional corepressor pathway causes Purkinje cell loss and cerebellar atrophy
clinical features: ataxia
SCA 1 (poly q)
gene: Huntingtin
Gene function: multifunctional
scaffold protein
for protein
interactions
pathogenic mechanism: gain function of toxic protein
pathology: N‐terminal polyQ fragments of mutant huntingtin form aggregates and interact and interfere with different proteins
clinical features: Atrophy of the striatum; choreiform movement
Huntington’s Disease
(polyQ) disease)
also as known as Lou Gehrig’s disease or classical motor neuron disease is a
neurodegenerative disease that affects both lower motor neurons in brainstem and spinal cord, and the upper motor neurons in the motor cortex: loss of these neurons leads to muscle atrophy and weakness
ALS
Amyotrophic lateral sclerosis and frontotemporal lobe degeneration are the same or different disease
same
ALS patients not only have motor symptoms but usually have ____ symptoms at some time during disease progression
FTLD
_____ is a pathological process that occurs in frontotemporal dementia (FTD)and is
characterized by frontal and temporal lobe atrophy with behavioral or language
abnormalities
FTLD
Some FTLD patients also have clinical pathological motor symptoms similar to those in ____ patients
ALS
*** 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 patients and FTLD patients have the same protein (____ & ____) inclusions
TDP43 and FUS
Many FTLD patients have neuronal inclusions containing TAR DNA‐binding protein
43 (______), similar to what is found in motor neurons of ALS patients
FTLD and ALS patients also have another same pathological accumulations, the
neuronal inclusions containing fused in sarcoma (_____) protein
TDP43; FUS
common genetic cause for ALS and FTLD, the chromosome ___ _____ ____ _____ ___ (C9ORF72) mutation, confirmed that ALS and FTLD are at opposite ends of the clinical spectrum of a single disease
chromosome 9 open reading frame 72
ALS and FTLD are the same disease with same or different clinical spectrums
different
what is the clinical phenotype for FTLD
FTD (frontotemporal dementia)
FTLP‐TDP pathology all resulting in _______ accumulation
TDP‐43
____ is an RNA‐binding protein that contains a prion‐like domain (a hydrophobic domain) and involved in regulation of RNA splicing
TDP‐43
____ is an RNA‐binding protein that contains a prion‐like domain and
involved in regulation of RNA splicing
FUS
Both TDP‐43 and FUS are shuttled between the ____ and _____: pathological events cause their retention in the
cytoplasm and accumulation
nucleus; cytoplasm
preferentially affect motor neurons (LMNs and UMNs) but may develop a frontotemporal syndrome
A multisystem disorder
<15% of ALS patients present the typical features of a ______
FTD
a specific hallmark of ALS
Bunina bodies
predominantly TDP‐43 immunoreactive
Skein‐like inclusions
what is the histopathology of ALS
- Bunina bodies
- skein-like inclusions
- basophilic inclusions
5.Astrocytic gliosis and microglial reaction (reactivegliosis)
which of the following neuronal types is involved in amyotrophic lateral sclerosis **ON EXAM
UMN, LMN, Frontal cortical neurons, temporal cortical neurons
bulbar or respiratory onset ALS has more or less malignant phenotype
more
cell death requires participation in what two things in ALS
microglia and astrocytes
most ALS patients have inclusions containing ubiquitylated and phosphorylated ____
TDP43
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
- motor and frontotemporal neurons are affected to variable degrees
- not all types of motor neurons are affected in ALS
- large spinal motor neurons are affected than smaller ones
neuronal vulnerability in ALS
- Differences in the stress‐coping capacity of different types of neurons
- Difference in regeneration potential of different types of neurons
- Spinal motor neurons are highly susceptible to glutamate‐induced excitotoxicity
- Spinal motor neuron are more susceptible to imbalance of calcium homeostasis
- Spinal motor neurons also have limited calcium‐buffering capacity
- Why neurons are particularly susceptible to TDP43 and FUS abnormalities
—–TDP43 and FUS are splicing factors bind to long intronic stretches of RNA and nervous tissue contains relatively longer intron‐containing transcripts than other tissues
Why some types of motor neurons are particularly vulnerable?
Mutations in _____ cause X‐linked fALS
UBQLN2
Sequestosome 1 (SQSTM1, aka ___) is a receptor for ubiquitylated proteins
p62
Genes/proteins involved in impaired protein degradation in ALS
UBQLN2, p62, VCP
*** 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
in ALS, only mutant superoxide dismutase 1 (SOD1) becomes misfiled and wild type SOD1 does not misfold
-contains (prion‐like domain) and binds single‐stranded DNA (sDNA) or RNA
-binds sDNA and RNA and is involved in transcription, RNA splicing and transport
-shuttles between the nucleus and the cytoplasm ———————– In the cytoplasm, it associated with stress granules in which RNA is translationally silenced and transported to a target site for translation
TDP43
During starvation or oxidative stress, TDP43 is mainly in the _____, where it is incorporated into stress granules and the glycine‐rich domain of TDP43 is necessary for its accumulation into stress granules through its prion‐like properties
cytoplasm
TDP43 causes pathogenesis in a two‐step manner:
- the exit of TDP43 from the nucleus
- the irreversible formation of stress granule aggregate –> resulting in gain of function (cytoplasmic aggregation) and loss function (abnormal RNA processing) pathogenic mechanism
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
- FUS is an RNA‐binding protein containing a prion‐like domain
- FUS uses transportin as a carrier to shuttle between the nucleus and cytoplasm
- Most FUS mutations cause FUS
mis‐localization in the cytoplasm, where it is recruited into stress granules that may form inclusions (basophilic inclusions) - depletion of FUS alters the splicing of mRNAs
Mutations in RNA‐binding proteins cause ALS‐FUS
TDP43 and FUS are both RNA‐binding proteins that contain a prion‐like domain which is necessary for ____ ____ formation
stress granule
- The prion‐like domain renders the aggregation propensity of these proteins
- The prion‐like domain in these proteins may also contribute to the
progressive, spreading nature of ALS — ALS usually affects regions in contiguity with the site of onset - Proteins with a prion‐like domain promote aggregation by acting as a template to induce the conversion of natively folded proteins and trap the normal protein in the aggregate
stress granule formation
proteins different from the mutant one can also be recruited in the aggregates
Cross‐seeding (co‐aggregation)
Nucleotide repeat expansion mutations between two transcription initiation sites in _____ cause 50% fALS
C9ORF72
_______ causing lost‐of‐function pathogenic effect
haploinsufficiency; loss of protein function
The expanded hexanucleotide repeat also forms nuclear RNA foci in neurons and may exert a deleterious gain‐of‐toxic RNA function effect, acting as a sink for nuclear RNA‐ binding proteins that then are unavailable for the correct splicing of other mRNAs
Gain of toxic RNA function
Another possible pathogenic mechanism could be repeat‐associated non‐ATG (RAN) translation, results in the accumulation of dipeptide repeat (DPR) proteins
gain of toxic protein function
dipeptide repeat proteins , poly(GA), poly(GP), and ploy(GR), were generated from repeat‐associated non‐ATG (___) translation from all three reading frames
RAN
Three possible pathogenic mechanisms:
(1) loss of GEF function of the protein
(2) gain of function of the toxic RNA
(3) gain of function of toxic protein (DPR proteins)
glial cells become increasingly activated and secrete inflammatory mediators as the disease progresses and modify disease process
Neuroinflammation
Cell death in ALS is ___-___ _____ as astrocytes and microglial cells that surround motor neurons contribute to disease onset and progression
non‐cell autonomous
in the mutant SOD1 mouse, ____ degenerate and loss of trophic support from _____ is toxic to motor neurons
oligodendrocytes
Factors involved in the ____ ____, ___ ____, ___ ____release are involved in the pathogenesis of ALS
cytoskeletal organization, cellular transport and synaptic vesicle
Cellular and molecular pathogenic events in ALS
- proteinopathy in ALS: impaired proteostasis
- RNopathy in ALS: impaired RNA metabolism
- glial cells cause inflammation modify disease process
- axonal architecture and transport fall
- progressive cellular failure and excitotoxicity
neuronal cell bodies and synaptic connections
Gray matter
(myelinated) axonal bundles or tracts/columns in the CNS
White matter
disease of the central nervous system
Immune‐mediated demyelinating
pathological hallmark of MS
focal areas of INFLAMMATION-MEDIATED DEMYELINATION and axonal transection/degeneration in the brain and spinal cord white matter
85% of MS patients begin with a disease phase characterized by neurological deficits
followed by recovery, termed _____ - ______ ____
relapsing‐remitting MS (RRMS)
- Relapse in RRMS is caused by focal areas of inflammatory demyelination
where myelin‐forming oligodendrocytes and axons are destroyed - Edema cause nerve conduction block
- Remission is due to
(i) resolution of the inflammation and edema
(ii) reorganization of axonal sodium channels on demyelinated axons
(iii) remyelination to restore axonal conduction
relapsing‐remitting MS (RRMS)
After one to two decades, majority of RRMS patients enter a second disease phase characterized by continuous irreversible neurological disability unassociated with relapses, term
secondary progressive state of MS (SPMS)
Irreversible neurological functional decline in MS patients is mainly caused by _______ ______ (NOT inflammatory demyelination)
axonal degeneration
15% MS patients have a ___ ____ ___(PPMS) with rare or no relapses
primary progressive MS
inflammatory demyelinating disease caused experimentally in rodents by inducing an immune response in animals to myelin components and is used as an animal model for MS
Experimental allergic encephalomyelitis (EAE)
The presence of inflammatory cortical demyelination in early MS advocates a _____ ____ ____at this stage of disease
primary neurodegenerative process
t/f MS is inherited
FALSE NOT INHERITED
The only consistent MS‐associated gene is the ______gene
HLADRB1
Environmental factors also contribute to MS disease susceptibility and _____ are the most implicated factor
viruses
MS brains show axonal ______ and loss or axonal retraction bulbs/axonal ovoids
transection
At later stages of MS, after oligodendrocyte death, loss of ____ ___ and alterations in axonal cytoskeleton and fast axonal transport may lead to axonal transection/degeneration
trophic support
Demyelination is mediated by _____ and monocytes/______
microglia; macrophages
- Substances in the inflammatory microenvironment could injure axons
- Nitric oxide synthase (iNOS) is upregulated in acute inflammatory MS lesions, resulting in increased nitric oxide (NO) level
— elevated NO is detrimental to axonal survival - Cytotoxic CD8+ T cells can mediate axonal transection in acute lesion
- Excitotoxicity
- Loss of trophic support and myelin from oligodendrocytes
Mechanisms of Axonal Degeneration in Acute Inflammatory MS Lesions
are cytotoxic CD8+ T cells involved in chronic or acute inflammatory MS lesions
acute
does genetics cause MS
no
irreversible decline in MS phase is caused by inflammatory effects t/f
false
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
MS lesions can also involve gray matter in addition to common white matter lesions
cortical demyelination
neuronal cell bodies and synaptic connections
gray matter
(myelinated) axonal bundles or tracts/columns in the CNS
white matter
white and gray matter lesions
type 1 lesions
extensive gray matter only lesions
type 3 lesions
t/f Cortical demyelination occurs with significant influx of hematogeneous leukocytes and lesions have intact blood‐brain barriers
f it is w/o significant influx of hematogeneous leukocytes
Gray matter (cortical) lesions contained fewer inflammatory cells, but few activated by microglia t/f
f, many are activated by microglia
t/f Cytotoxic T cells are significantly more in MS white matter lesions than in cortical lesions
t
Cortical demyelination is probably not directly caused by immune cells (such as macrophages or CD8+ cytotoxic T cells) but could instead be caused by _____
microglia
myelin is removed by _____ in cortical lesions
microglia
axonal degeneration continue in environments other than the inflammatory demyelinating lesion
Chronic demyelinating lesion
In addition to insulation of myelin sheath, _____ provide trophic support that is essential for long‐term axonal survival
oligodendrocytes
Two parallel mechanisms of axonal degeneration: imbalance between energy supply and demand
what is the mechanism
- limited energy supply due to ischemic/hypoxia insults of white matter
- demyelination increases the energy demand of nerve conduction
—-restores nerve conduction by the expense of increased energy demand - Axoplasmic ATP production eventually becomes compromised in the chronically demyelinated axon, leading to an ionic imbalance that increases axoplasmic Ca2+, which eventually destroys the axon
Degeneration of chronically _____ axons is a major contributor to neurological disability and brain atrophy
demyelinated
Remyelination is the ____ response to demyelination
recapitulation hypothesis
- migratation and proliferation
- differentiation and maturation into myelin forming OLs
- myelinated axons
Recapitulation hypothesis
G ratio is ______ in remyelination
increased
In developmental myelination, _____ diameter axons are enwrapped with proportionally _____ myelin
in remyelination, the myelin sheath length and thickness remain roughly constant _____/_____regardless of the axon diameter
larger, thicker ; thinner/shorter
- Patterning and Specification
2.Sonic hedgehog (ventralizing signal) - neural stem cells express Olig2
- neural stem cells specify to become OPCs
Patterning and Specification pathway
- OPC activation
- Microglia, Astrocyte &
inflammation - injury signals
- OPCs upregulate Olig2 activation of OPCs
OPC activation pathway
*** T/f G ratio is decreased in demyelination
false; it is increased
- Proliferation and Migration
- PDGF & FGF
Proliferation and Migration pathway
- I. OPCs are activated by acute injury induced signals produced from MICROGLIA and ASTROCYTES
——2. OPCs change morphology (HYPERTROPHY) and up regulation of several genes –> transcription factors OLIG2
Activation of adult OPCs
- activated MICROGLIA and ASTROCYTES are major sources of OPC mitogens and chemotaxic factors
Recruitment or migration, and proliferation of adult OPCs
- Differentiation and maturation of OPCs into remyelinating oligodendrocytes
expression of depression + activation of myelin genes
expression of depression + activation of myelin genes
stages of remyelination
- activation
- recruitment, migration, + proliferation
- differentiation and remyelination
Platelet‐derived growth factor (PDGF) and insulin‐like growth factor 1 (IGF‐1) are ____ ____
OPC mitogens
_____acts as a chemokine and inhibits differentiation and promote recruitment (migration)
FGF
- The role of the innate immune response to demyelination is to create an environment conducive to remyelination
- Phagocytic macrophages play a critical part in the removal of the myelin debris as CNS myelin contains proteins that inhibit OPC differentiation
Inflammatory response plays a key role to promote remyelination
activation of _____ pathway inhibits OPC differentiation
Notch
____ _____ is also a negative regulator of OPC differentiation and regulates kinetics (timing) of OPC differentiation
WNT signaling
transcription factor such as ____has key roles in OPC development and differentiation in remyelination
Olig1/2
***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
- An impaired macrophage response in aging and a delay in the expression of inflammatory cytokines and chemokines lead to POOR CLEARANCE OF MYELIN DEBRIS
- GROWTH FACTOR RESPONSIVENESS OF ADULT OPCs IS DECREASED IN AGING
- in old animals HDAC RECRUITMENT IS IMPAIRED, resulting in prolonged expression of these inhibitors, delayed OPC differentiation
Non‐disease‐related factors for remyelination failure
____ expression to recruit of HDACs to downregulate inhibitors
YY1
downregulate inhibitors
In older animals, recruitment of _____ to the promoters of the
inhibitory molecules is impaired, resulting in a environment that is skewed towards the inhibition of myelin genes
HDACs
Disease‐specific factors for remyelination failure
- Dysregulation (hyperactivation) of Notch or Wnt pathway could delay OPC differentiation
- missing a critical window of opportunity for remyelination
