Exam 4 Flashcards
primary motor symptoms of PD
- bradykinesia: slowness and lack movement
- tremor at rest
- rigidity
- flexed posture and postural instability
cardinal feature of PD
bradykinesia
almost all have
secondary motor symptoms of PD
- freezing of gait
- micrographia
- mask-like expression
why do PD patients have micrographia
difficult to concetrate on the size of the writing and the thing they are writing
non motor features of PD
- sleep disorders
- autonomic function
- sensation loss
- cognitive impairment
- mood
autonomic function problems in PD are likely due to
denervation
main neuropathological hallmarks of PD
- loss of dopamenergic neurons in the SNpc
- loss of pigmented neurons in the SNpc
- lewy bodies
The motor symptoms of PD result from the loss of which neurotransmitter?
dopamine
Which neurons are most severely lost in PD patients?
Neurons in the Substantia nigra Pars Compacta
if dopamine is lost in PD, why do treatments use L-Dopa?
- dopamine is too big to cross the BBB
- dopamine broken down too quickly
- L-Dopa does not do these things
therapeutic targets to improve dopamine neurotransmission in PD
- viral expression of tyrosine hydroxylase (makes L-Dopa)
- expression of AADC (makes dopamine)
- MAO/COMT inhibitors
- DAT inhibitors
- DA receptor agonists
MAO/COMT does what
breaks down dopamine
PD treatment by using DA receptor agonists helps because
dopamine is relased more since the receptors don’t signal that it is not needed anymore
PD treatment by using DAT inhibitors helps because
DAT not there to uptake dopamine
critical advancements in discovering PD
- DA recognized as a neurotransmitter
- MPTP usage by addicts causing parkinson’s like symptoms
- genetic causes discovery
MPTP is
a prototypical DAergic toxin
* causes degeneration of DAergic neurons
how does MPTP cause loss of DA neurons
- MPTP crosses BBB
- MPTP turned into MPP+ by MOA-B in astrocytes
- MPP is uptaked via DAT into mitochondria
- oxygen free redicals and energetic failure in mitchondria = cell death
current therapies for basal ganglia circuit in PD
- DA or cell therapy replacement
- surgical pallidotomy
- DBS
Deep brain stimulation treats the motor symptoms of Parkinson’s Disease patients by:
interfering with signals in the basal ganglia circuit in the brain
PD has loss of D1 or D2 neurons
D1
Mutations in which of the following genes is not considered a monogenic cause of PD?
SNCA
PINK1
GBA
LRRK2
GBA
Which genetic mutations is the most common cause of PD?
IMPORTANT - MIGHT BE ON EXAM
LRRK2
IMPORTANT - MIGHT BE ON EXAM
Which genetic mutations is the most common cause of PD?
IMPORTANT - MIGHT BE ON EXAM
LRRK2
IMPORTANT - MIGHT BE ON EXAM
According to Braak, where does alpha-synuclein pathology (Lewy Bodies) first appear in the CNS of PD cases?
Dorsal Motor Nucleus of Vagus
10% of PD cases are
genetic
Parkin mutations are _ _
autosomal dominant
genes involved in PD that mutate
- SNCA
- PINK1
- DJ-1
parkin is a _ that is important in _
E3 ligase important for Ub tagged degredation
PINK1 mutations are
autosomal recessive
PINK1 normally has a _ and function to _
mitochondrial targetting motif and localizes to mitochondria
PINK1 regulates
mitochondrial fussion/fission
in animals, deletion of PINK1 led to
muscle atrophy
in animals, deletion of PINK1 was corrected by
overexpression of Parkin
PINK1 normally _ parkin
recruits and activates parkin
parkin/pink 1 mutations have:
* onset
* symptoms
* degeneration
* pathologies
- onset before 40
- slow or no symptoms
- selective degeneration of SNpc and locus coeruleus neurons
- no lewy bodies or tau pathologies
Parkin/PINK1 knockout mice features
- no neurodegeneration
- loss of DA neurons sometimes
- no increase of vunerability of DA neurons ot MPTP or synuclein toxicity
- overexpression of parkin protexted DA neurons from MPTP and alpha synuclein toxicity
overexpression of parkin…
protected DA neurons from MPTP and alpha synuclein toxicity
DJ-1 is what type of mutation
point mutation
L166P mutant is in what gene
DJ-1
DJ-1 knockout mice have severe or mild phenotype
mild
SNCA mutations are _ _
autosomal dominant
synuclein normally functions
as a synaptic chaperone
* important to inhibition of vesicle release (inhibit neurotransmitter release)
alpha synuclein antibodies…
recognize lewy bodies
lewy bodies are composed of
fibrillar alpha synuclein
alpha synuclein aggregates form
lewy bodies
two other types of alpha synucleinpathies
- dementia with lewy bodies
- multiple system atrophy (MSA)
what parts of the brain show Lewy Bodies in PD
Hippocampus
Locus Coeruleus
Vagal Nerve
IMPORTANT
Toxic conversion of alpha-synuclein is thought to involve:
formation of beta sheet structures
IMPORTANT
Which of the following are genetic risk factors for sporadic PD?
APP
PINK1
Parkin
MAPT
MAPT
IMPORTANT
synucleins inhibit
neurotransmitter release
alpha synuclein antibodies recognize
lewy bodies, lew neurites and GCIs
in SMA and dementia in lewy bodies, alpha synucleinopathies occur in
oligodendricytes
in SMA and dementia in lewy bodies, alpha synucleinopathies occur in
oligodendricytes
alpha synuclein pathology in PD initiates from _ and moves _
the brainstem and moves anteriorally
expression of A53T Hu alpha syn leads to
fatal neurological disease in Tg mice
human alpha synuclein transgenic mice features
- sudden onset
- rapid progession
- within 10 days, catatonic
expression of A53T Hu alpha syn
causes neurodegeneration in DA neurons
LRRK2 is important to
innate immunity
membrane trafficking
other things
gene important in PD
LRRK2 is important to
innate immunity
membrane trafficking
other things
gene important in PD
homzygous loss of function in _ causes Gaucher disease
GBS
LRRK2 pathology
- lewy bodies
- alpha syn aggregates
- extran SN degeneration
LRRK2 mutation are _ inheritance
autosomal dominant
PD
LRRK2 mutation PD has clinical pathology
- progressive
- common non motor abnormalities
- dementia
PRKN PINK 1 and DJ1 inheritance
autosomal recessive
PRKN PINK DJ 1 mutations pathologies
- no lewy bodies
- selective SNpc degeneration
clinical PRKN PINK1 DJ1
- slowly progressive
- limited non motoric abnormalities
lack of GBA causes dysfunction in
the lysosomes
PD
lack of GBA causes dysfunction in
the lysosomes
PD
genes that are heriditary PD
- LRRK2
- PRKN
- PINK1
- DJ-1
genes that are sporadic PD risk
- SNCA
- GBA
pathology of sporadic PD
- lewy bodies
- alpha syn aggregates
- SNpc and SN degeneration
clinical features of sporadic PD
- progressive
- common non motoric abnormalities
- dementia
targets for PD treatment
- alpha syn aggregates
- targets of alpha syn aggregates
many clinical defects of PD do not respond to
DA replacement therapy
LRRK2 mutation increases
alpha syn in glia (astrocytes, microglia)
if PD starts in the gut, alpha syn is carried ot the brain via
vagal nerve
a vagotomy _ in PD
decreases the risk of developing PD
injection of al[ha syn in the gut in animal models let to _ unless
led to alpha syn in the brain unless the vagal nerve was cut
CNS pathology after initiation of alpha syn in the gut is first seen in _ and leads to
DMV, leads to progressive loss of SNpc DA neurons
PD
alpha syn pathology in the ER
- ERAD defect
- ER caspase 9 and 3 activation
**lack of P-eIF2a activation
**
P-eIF2a activation is important for
protecting the ER from stress
PD
salubrinal
inhibits dephosphorylation of P-eIF2a
* protects cells from ER stress
ER derived alpha syn oligomers are
- highly pathogenic in animal models (very toxic)
a syn pathology activatives c-Abl which leads to
impairment of p53 dependent autophagy by inhibiting Mdm2
nilotinib
treatment that inhibits c-Abl so inhibits the inhibition of p53
* works to help a little in animal models
PD
nilotinib
treatment that inhibits c-Abl so inhibits the inhibition of p53
* works to help a little in animal models
PD
prion diseases can be
- aquired
- genetic
- sporadic
prion diseases manifest as
rapid progressive demtias with clinical visual or cerebellar signs and mutism
sporadic, iatrogenic and familial CJD symptoms
progressive dementia and neurological signs
variant CJD symptoms
early psychiatric symptoms, neurological deficits and cognitive decline
GSS symptoms
cerebellar dysfunction
pathological characteristics of prion diseases
- brain vacuolation (holes)
- astrogliosis
- neuronal cell death
- PrP amyloid plaques
general structure of prion
- 2 charged clusters
- octapeptide repeat protein
- hydrophobic domain
- glycosylations
- protein with GPI anchor
prion cleavage sites and when
- alpha - occurs normally
- beta and gamma - occurs during stress
sCJD has _ PrP plaques
little to none
kuru has _ Prp plaques
some/medium
vCJD has _ PrP amyloid plaques
a lot
list the types of CJD with little to alot plaques in order
sCJD, kuru, vCJD
prion strains affect/are different in
- shape of aggregates
- what brain regions they’re in
- what disease they’re involved in
prion strains affect/are different in
- shape of aggregates
- what brain regions they’re in
- what disease they’re involved in
sCJD has _ prion strains
no coexisting prion strains
sCJD has _ prion strains
coexisting prion strains
vCJD has _ prion strains
coexisting
statistics of prion diseases
- rare
- older incidence
- white people
entry sites of acquired prion diseases
- intracranial
- coreal
- airway
- ingestion
- intramuscular
- intravenous
the passage of prions from one species of the other is _
inefficient
species barrier
prion diseases dont pass easily between species, absolute or partial transmitssion
models for the confirmational conversion of PrPc into PrPsc
- template directed refolding
- seed nucleation
early change in PrP toxicity
removal of synapses
PrP overexpressing transgenic mice features
- neuronal loss
- PrP Sc deposits
- Gliosis
- Premature death
in Prion diseases, see _ in MRI DWI
cortical ribbons
PSWC in Prion diseases shows
??
EEG
biomarkers in CSF in prion diseases
- 14-3-3
- Tau
CUrrent strategies of treatment of prion diseases
- Prnp knockdown (prion production)
- antibodies to prevent prion conversion
- antibodies to prevent prion aggregation
- compounds to interfere with neurotoxicity
the primary determinants of TSEs are
- primary sequence of PrPc
- route of entry of PrP Sc
_ are good noninvasive biomarkers of prion diseases
- cortical ribbons
- PSWC
which codon polymorphisms increase chance of prion infections
codon 129
familial CJD defined by
- CJD
- CJD in family member
- disease causing PRNP mutation
brain stroke is a condition that occurs when
there is not enough blood flow to the brain to meet metabolic demand
* leads to limited oxygen supply and death of brain tissue
_ strokes are more common
isochemic
ischemic strokes are due to
blockage of blood vessel
hemorrhagigc strokes are due to
bleeding around the brain
most common symtoms of stroke
all are sudden
* numbness of face arm or leg
* confusion
* trouble seeing
* dizziness
* severe headache
arteries bringing blood to the brain
- internal carotid artery
- vertebral artery
- the circle of willis
middle cerebral artery
- covers 80% of lateral surface of the brain
- common site of occlusion
anterior cerbral artery
- mostly supplies the midline of both cerebral hemispheres
posterior cerebral artery
- supplies the parietooccipital and temporal cortices
advantage of the circle of willis
- connects everything so if there is occulusion other branches can provide blood to the vital areas
the major arteries giving blood to the brain make up the
circle of willis
ischemic penumbra
outside part of affected region by stroke
* can recover after if treatment is fast enough
* will become core (dead) if not fast enough
in stroke, tissue outcome depends on
- severity of flow reduction
- duration of flow reduction
statistics of stroke
- very common cause of death
- aging is a risk factor
- leading cause of disability
CADASIL
- inherited form of cerbrovascular disease
- occurs when the thickening of blood vessel walls blocks the flow of blood to the brain
- genetic risk factor for stroke
CADASIL
- inherited form of cerbrovascular disease
- occurs when the thickening of blood vessel walls blocks the flow of blood to the brain
- genetic risk factor for stroke
imaging used to see stroke
FLAIR MRI
CADASIL mutation causes
- mutation in substrate for gamma secretase (NOTCH 3)
ischemic cascade in the core
- ENergy failure (decrease in ATP)
- decrease in Na/K ATPase
- anoxic deplarization (constant APs)
- increased glutamate release
- excitotoxicity
penumbra ischemic cascade
stress increases glutamate release
* leads to excitotoxicity, apoptosis and necroptosis
temporal sequence of events in cerebral ischemia
- excitotocity within minutes, falls at hours
- release of GABA to inhibit glutamate during exocitocity
- depolarization constant whole time
- inflammation after hours
- necroptosis and apoptosis increase as time goes on
mechanisms of ischemic cell death in the brain
- activation of cytokines, proteases
- cell swelling
- excitoxicity
- transmigration of immune cells
stages of excitotoxicity
- initiation: increase in glutamate
- amplification release of Ca and Ca up in cell
- expression: ROS, RNS, swelling, yeet cell
proinflammatory cytokines
- IL 1, 6, TNF
cell death and immune response in isochemic
- proinflammatory responses
- proinflammatory cytokines
- leukocyte infiltration
- tissue damage
resolution of inflammation and tissue repair
- clearing dead cells with “eat me” and “find me” signals
- releasing anti inflammatory cytokines (IL 10, TGF beta)
- brain repair (MMPs)
rt-PA (activase)
- clot buster
- drawback: need to administer within 3 hours and only worls for isochemic stroke
current strategies of stroke treatment target
- oxidative stress
- excitotoxicity
- apoptosis
- inflammation
- energy deficit
_ plays a key role in ischemic mechanisms
inflammation
cell death type in infarct core
necrosis
two broad groups of cerebrovascular disease
- ischemia
- hemorrhage
potential ways to harness the human microbiome
- stool from two groups then analysis
- put stool from patients in animal modes and behav anal
- transfer healthy stool to patients and behav analy
- control diet of patients
98% of the gut biome
- firmicutes
- bacteroidetes
estabilishment and maintainence of gut colony
- high variability in infancy
- higher diversity in species as we age
estabilishment and maintainence of gut colony
- high variability in infancy
- higher diversity in species as we age
the microbiota gut brain axis
bidirectional communication
* HPA axis
* bacteria release neurotransmitters and neuropeptides, microbial by products and metabolites, cytokines, bacterial debris
the microbiota gut brain axis
bidirectional communication
* HPA axis
* bacteria release neurotransmitters and neuropeptides, microbial by products and metabolites, cytokines, bacterial debris
microbiome and aging
- aging affects microbiomes and their products which effects intestinal properties
- which causes increased frailty, inflammaging, release of proinflammatory cytokines, increased blood pressure
microbiome and aging
- aging affects microbiomes and their products which effects intestinal properties
- which causes increased frailty, inflammaging, release of proinflammatory cytokines, increased blood pressure
centenarians have an
overall higher diversity in their microbiome, but not necessarily the same as the young microbiome
centenarians have an
overall higher diversity in their microbiome, but not necessarily the same as the young microbiome
centenarians have an
overall higher diversity in their microbiome, but not necessarily the same as the young microbiome
centenarians have an
overall higher diversity in their microbiome, but not necessarily the same as the young microbiome
centenarians have an
overall higher diversity in their microbiome, but not necessarily the same as the young microbiome
germ free mice never
develop mature microglia
the microbiome affects microglial maturation and activation
microbiota secrete
ROS scavengers
* short chain fatty acids
* ferulic acid
microbial dysbiosis
leaky gut so increase in proinflammatory molecules which increases BBB ermeability which causes oxidative stress in CNS
_ shows lewy body pathology first in PD
dorsal motor nucleus of CN10
_ starts to show lewy body pathology in PD stage 3
substantia nigra
dual hit staging hypothesis
PD pathology originates from insults in the peripheral organs where alpha syn is seeded before translocating to the brain
patients with IBS show
an increased incidence of PD
evidence for the dual hit staging hypothesis
evidence for dual hit staging hypothesis in animal models
- gut microbes promote alpha syn mediated motor deficits and brain pathology
- depletion of gut bacteria reduces microglia activation
- human gut microbiota from PD patients enhanced motor dysfunction in mice
limitations of microbiota research
- defing normal and healthy gut microbiota
- understand the effect of lifestyle
- define directionality between cause and effect
- understand the contribution of gene enviroment impacts
- understand the effect of lifestyle
gut microbiome
A collection of microorganisms, viruses, and fungi, their genes and genomes
There has been evidence for a role for the microbiome in which of the following disorders?
Parkinson’s Disease
Alzheimer’s Disease
Multiple Sclerosis
Amyotrophic Lateral Sclerosis
primary pathways by which the gut microbiome may modulate neurodegenerative diseases
- The immune system
- The vagus nerve
- Microbial metabolites in circulation