module 3 Flashcards
what is multiple sclerosis
autoimmune disorder with antibodies against myelin
- consequently damages neurons in the CNS
what are some symptoms of MS
optic neuritis
sensory loss
muscle weakness
pins&needles
(starts with sensory symptoms first)
what are three ways MS is diagnosed
lesions seen in MRI
spinal tap (antibodies detected in the CSF)
electrical potentials to measure speed of AP
what are the 4 clinical courses of MS
relapsing remitting MS (RRMS)
secondary progressive MS (SPMS)
primary progressive MS (PPMS)
primary relapsing MS (PRMS)
what is relapsing remitting MS (RRMS)
occurrence of relapses at irregular intervals with complete or incomplete neurological recovery
(~85% of patients)
what is secondary progressive MS (SPMS)
progressive, irreversible disability that occurs independently of the presence of relapses
what is primary progressive MS (PPMS)
gradual worsening without relapses/attacks
what is primary relapsing MS (PRMS)
progressive disease from the onset, acute relapses and periods of continuing progression between relapses
(rare)
is new myelin formed during remyelination as efficient as original myelin
no, remyelination produces thinner myelin sheaths
what is the relationship between epstein-barr virus and MS
EBV infection during 10yr-45yr increases MS risk 32 fold
several EBV antigens are the target of cross-reactive autoantibodies found in MS
where is myelin degenerated in MS
only myelin formed by oligodendrocytes (CNS)
where do t cells develop and mature
develop in bone marrow and mature in thymus where they acquire specific receptors
what kinds of T cells are deleted during development
T cells with receptors that have a strong affinity for self antigens
what are T regulatory cells (Trergs)
inhibit T cells that have a strong affinity for self-antigens in the periphery
what are Treg cells crucial for
preventing autoimmunity
how are T cells and B cells activated
- naive helper T cells engage MHC II molecules on antigen presenting cells (APC) and become activated
- clones of activated helper T cell activate B cells and cytotoxic T cells
- cytotoxic T cells produce enzymes that lyse the infected cells
what is a CD4+ T cell
helper T cell
what is a CD8+ T cell
cytotoxic T cell
what kind of cells are antibody secreting cells
B cells
how many types of antibodies does a B cell make
one kind
what activates B cells to produce antibodies
activated helper T cells activate B cells
what are memory cells
a few T and B cells that remain after the infection
what 2 things are seen in the CSF of 95% of MS patients
clonal bands of IgG antibodies (against myelin antigens)
antibodies to glial proteins, aquaporins and potassium channels
what do some antibodies against myelin cross-react against
EBV antigens
have there been any specific antigens identified that are responsible for MS
no
what happens in MS if there is a depletion of B cells
helps symptoms
what is a consequence of demyelination in MS
action potentials decay before reaching the presynaptic terminal because they have to cross stretches of demyelinated axons
what causes organelles to aggregate (blebs) in MS
axonal transport along microtubules is disrupted in demyelinated axons which can cause organelles to aggregate
what are 5 treatments that can be done to help the immune system in MS
- glucocorticoids
- interferons: alter the balance of T helper and T reg cells
- rituximab: destroys B cells in circulation
- plasmapheresis: remove plasma, deplete antibodies, put it back
- reduce T/B cells in circulation
what are two other treatments (not to do with immune system) for MS
compete with myelin for binding sites on immune cells
block potassium channels
what are the two centers of the brain that are considered upper motor neurons
motor cortex: voluntary movements
brainstem centers: movements, posture control
what are the two brain areas that modulate and fine tune movement
basal ganglia: initiation of intended movement and suppression of unwanted movement
cerebellum: coordination of ongoing movement
where are lower motor neurons found
ventral horn of spinal cord
what does a lower motor neuron look like
one alpha motor neuron branches and innervates many muscle fibers
what is a motor unit
one alpha motor neuron (in ventral horn of spinal cord) and the muscle fibers it innervated
what is a motor neuron pool
all the motor neurons innervating a muscle
what is the order of events that occurs at the neuro-muscular junction
- ACh released from presynaptic terminal
- nAChRs (ion channels) are activated
- muscle is depolarizes and fires AP
- muscle contracts
(DRAW)
what is muscle tone
the basal level of contraction maintained at all times that allows the muscle to both stretch and contract
what is the neuromuscular spindle
a sensory receptor (organ) that senses the length/stretch of muscle fibers
what is myasthenia gravis
autoantibodies against postsynaptic nAChRs
what is lambert eaton myotonia
autoantibodies against presynaptic voltage-gated calcium channels
what is spinal muscular atrophy (SMA)
rapid degeneration of lower motor neurons
what are the genetics of SMA
autosomal recessive
deletion or loss of function mutations in survival of motor neuron (SMN) gene
what does the survival of motor neuron (SMN) gene do
encodes a protein involved in the assembly of snRNPs
- mutations result in splicing defects especially in lower motor neurons
what are symptoms of SMA
severely reduced muscle tone
(affected children never sit/stand)
respiratory failure before age 2
what is the treatment for SMA
antisense drug that modulates alternate splicing of the SMN2 gene, functionally converting it into SMN1gene, thus increasing the level of SMN protein in the CNS
what are Betz cells
large pyramidal neurons that are found in layer V of the motor cortex
- largest neurons in the brain
what connections do Betz cells form
direct connections with alpha motor neurons in the spinal cord
(other connections are mainly to interneurons in the spinal cord)
what is the function of Betz cells
initiate and modulate voluntary movement by activating lower motor neurons that supply distal limbs
- essential for fine motor control
what is the ventral corticospinal tract
cortex to brain stem to spinal cord
- fibers do not decussate
- terminate bilaterally in medial spinal cord and over many segments
- control posture
what is the corticobulbar tract
from cortex to cranial nerve nuclei in midbrain, pons, and medulla
what is the lateral corticospinal tract
direct pathway from cortex to spinal cord
- decussate in medulla
- terminate laterally
- control limbs and fine movement
what are the strength effects of LMN and UMN syndrome
LMN: weakness or paralysis
UPN: weakness
what are the muscle bulk effects of LMN and UMN syndrome
LMN: severe atrophy
UMN: mild to no atrophy
what are the reflex effects of LMN and UMN syndrome
LMN: hypoactive superficial and deep reflexes
UMN: hyperactive deep reflexes after initial period of spinal shock
what are the special signs and symptoms of LMN syndrome
initial signs/symptoms persist
fasciculations and fibrillations
geographic distribution of impairment
impairment of reflexive and gross and/or fine voluntary movements
what are the special signs and symptoms of UMN syndrome
initial period of spinal shock, then spasticity ensues
babinski sign and clonus
more widespread (nongeographic) distribution of impairment
impairment of fine voluntary movements; gross movements relatively unimpaired
what is ALS
heterogeneous disorder with degeneration of both upper motor neurons and lower motor neurons
brain loses its ability to initiate and control voluntary movements
what are the early symptoms of ALS
muscle weakness with flaccidity (LMN damage)
sometimes difficulty speaking and dysphagia
what are later symptoms of ALS
muscles gradually weaken, fibrillations, fasciculations, atrophy
gradually all voluntary muscles are affected and lose ability to speak, eat, move, breathe
what is amyotrophic mean
muscle wasting
what are the 4 main genes associated with ALS
SOD1 (transcription factor)
FUS (RNA binding protein)
TDP-43 (RNA binding protein)
C9orf72 (open reading frame gene that can cause a repeat expansion in interon)
what is SOD1
a transcription factor
what can TDP-43 mislocalization cause
aggregate formation in motor neurons of the spinal cord of ALS
how does SOD1 regulate expression
- upon activation, it is phosphorylated
- phosphorylated SOD1 accumulated in nucleus
- SOD1 binds to promoters and regulates expression of genes involved in oxidative stress responses (ex. antioxidants and DNA repair proteins)
what happens to SOD1 in ALS
it is misfolded and aggregated
- aggregates are found in nucleus and cytoplasm where phosphorylation is disrupted
what is the role of chaperone proteins
help proteins fold into correct 3D structure
what happens to misfolded proteins
they are shunted to degradation pathways
what is the sequence of events that occurs in the ubiquitin proteasome pathway for degradation of misfolded proteins
- misfolded protein is tagged with ubiquitin
- the proteosome complex (filled with enzymes) destroy the target protein
- ubiquitin that was attached is released to be recycled
what are autophagosomes
membranes that fold around proteins or mitochondria that need to be degraded
- then fuses with a lysosome that contains enzymes to destroy targets
what is an ALS mutation that affects degradation
C9orf72 - regulator of autophagy initiation
- mutation results in diminished ability to degrade misfolded proteins
what two genes are substrates of autophagy and are involved in ALS
SOD1 and TPD43
- suggest that defective autophagy contributes to the toxic accumulation of these proteins in ALS
what are 6 cellular deficits associated with ALS
- protein homeostasis (disturbances in protein quality control)
- hyperactivation of microglia
- diminished energy supply
- excitotoxicity from reduced glutamate uptake
- disturbances in RNA metabolism
- altered axonal transport
what are two specific treatments for ALS
- Na+ channel blocker
- limits Glu release and excitotoxicity - antioxidant
- has some reduction in symptoms
do basal ganglia have direct connections to the spinal cord
no
do deficits in basal ganglia lead to paralysis
no, but can lead to involuntary movements or immobility without paralysis
what are the effects of movement from the basal ganglia in Parkinson disease and Huntington disease
Parkinson: diminished movement
Huntington: excessive movement
besides movement, what other deficits are basal ganglia involved in
cognitive/behavioral
what are the motor areas of the basal ganglia
striatum: caudate and putamen
pallidum: globus pallidus, substantia nigra pars reticulata
subthalamic nucleus
what comprises the ventral striatum
nucleus accumbens
(non motor area)
how many non motor circuits does the basal ganglia have
2
what is the main cell of the striatum
medium spiny neurons
what is the main modulator of cortical input to the striatum
dopaminergic input from substantia nigra pars compacta and VTA onto medium spiny neurons
what kind of output do medium spiny neurons have on globus pallidum and substantia nigra pars reticulata
GABAergic
what would happen if a synapse that was originally on a dendritic shaft was moved to the end of a dendritic spine
the influence on the neuronal signal would be lessened
what kind of output does the thalamus have on the motor cortex
glutamatergic output to motor cortex which then has excitatory input on cerebellum and other motor pathways
how does the direct pathway inhibit the thalamus
caudate/putamen is low activity
globus pallidus is high activity and secretes GABA which inhibits the thalamus
what neurotransmitter facilitates the expression of movement
dopamine
what does dopamines ability to increase or decrease excitability depend on
the receptor type
what is the difference between D1 and D2 receptors
D1 increase cAMP levels
D2 decrease cAMP levels
(both GPCRs)
what is focused selection in relation to basal ganglia
suppression of competing motor programs that could interfere with the expression of sensory-driven or goal-directed behaviors
what does dopamine do to the direct and indirect pathways
dopamine activates the direct pathway through D1 receptors and inhibits the indirect pathways through D2 receptors
what is parkinsons disease
loss of dopamine input to striatum due to degeneration of dopaminergic neurons
how does the loss of dopamine in parkinsons affect the basal ganglia and movement
D2 receptors will not inhibit indirect pathway so there is a overactivity (less movement)
D1 receptors will not enhance direct pathway (less movement)
- leads to sluggish movement, failure to initiate movement, and lack of control of the size of movements
what are some motor symptoms of parkinsons disease
rigidity, bradykinesia, balance/coordination problems,, resting tremors
(symptoms usually affect one side more than others)
what are non motor symptoms of parkinsons disease
changes in executive function, depression, anxiety, dementia, altered behavior, impaired sense of smell
what is neuromelanin
polymer pigment found primarily in the dopaminergic neurons of human substantia nigra
-increase with age
what kind of proteins does neuromelanin contain
proteins that bind metals like zinc and iron that scavenge reactive metals and other toxins
what are lewi bodies
formed by accumulation of alpha-synuclein that eventually fill cell body
what is the function of alpha-syniclein
modulates the SNARE complex that is important for synaptic vesicle release
- normally binds to synaptobrevin and regulates availability of synaptic vesicles for release
what is the role of Parkin and PINK1
proteins that recognize and destroy damaged mitochondria but after mutation they are unable to remove faulty mitochondria which continue to produce ROS
what happens when alpha-synuclein is mutated or aggregated
it cannot function and vesicles cannot be released from synaptic terminal
what is the structure of alpha-synuclein
in membranes, alpha helicies but overexpression, abnormal phosphorylation, or modifications of ROS result in the protein assuming a beta pleated structure
what system has a reduced function in lewi bodies
proteasome-ubiquitin system
how do dopaminergic neurons in substantia nigra pars compacta have a high rate of tonic firing
changes in calcium levels
what is a prion
misfolded protein
what does a prion-like mechanism refer to
the fact that prions can interact with normal proteins and cause them to misfold
- autophagosomes get overwhelmed with too many misfolded proteins and start to aggregate which causes the flow around axons and microtubules to be blocked
what are four treatments for parkinsons disease
L-DOPA: converted to dopamine in neurons
dopamine agonists
dopamine reuptake inhibitors
deep brain stimulation: near thalamus
what are 4 of the protein mutations that cause parkinsons
alpha-synuclein
LRRK2
Parkin
PINK1
what is an animal model treatment for PD
MPTP is a lipid soluble toxin that crosses the BBB and glia convert it into a form that is transported into neurons by dopamine transporters
it inhibits ETC and mitochondria eventually die
what is huntingtons disease
autosomal dominant disorder that leads to progressive degeneration of striatum
what are early motor symptoms of huntingtons
chorea (spastic, abnormal involuntary movement)
athetosis (writhing in distal extremities)
what are early non motor symptoms of huntingtons
mood swings, depression, learning and memory problems, decision making problems, change in personality and suspiciousness
what are some late symptoms of huntingtons
concentration problems, trouble eating and swallowing
what is the gene involved in huntingtons
htt gene on chromosome 4 codes for HTT (protein)
what change in repeats in mutated htt leads to huntingtons disease
increased number of CAG repeats (coding for glutamine) in mutated htt (mhtt)
what happens to successive generations with huntingtons disease
due to the DNA pol not being able to move smoothly over the stretch containing CAG repeats, it adds extra CAGs with each replication cycle causing successive generations to get huntingtons symptoms earlier
what in the basal ganglia is changed with huntingtons
there is degeneration of D2 containing medium spiny neurons which results in:
- less inhibition of caudate/putamen
- less inhibition of globus pallidus external
- more inhibition of subthalamic nucleus
- less excitation of globus pallidus internal
- less GABA release on thalamus
- disinhibition of thalamus leads to increased unwanted movement
what are some of the functions of huntintins protein at the synapse and synaptic transport
regulates axonal and dendritic transport
regulates endocytosis and exocytosis (quantity and rate of NT release)
regulates synaptic receptor stabilization at the post synaptic neuron
what are some of the results of a huntintins protein mutation at the presynaptic terminal
less endocytosis
fewer synaptic vesicles
less release of NT
what are some of the results of a huntintins protein mutation at the postsynaptic terminal
fewer receptors at post synaptic density
fewer signaling molecules
disrupted receptor clustering
disrupted receptor localization
does the striatum produce BDNF
no it depends on BDNF delivered by cortico-striatal afferences
how does HTT (protein) regulate BDNF delivery to striatum
- transcription regulation
- regulates transport of BDNF down cortico-striatal axons
- BDNF released at the synapse binds TrkB receptors and HTT stimulates endocytosis of BDNF at striatal synapse
- retrogradely transports BDNF to soma of striatal neuron
how does HTT regulate transcription of BDNF
REST represses transcription of the BDNF gene by binding to a silencer region in DNA
HTT normally binds REST (repressor) and sequesters it in the cytosol so BDNF is transcribed
mHTT cannot bind REST as well and BDNF is not transcribed
what are inclusion bodies
found in huntingtons disease and contain aggregates of mutant huntingtin (mHTT) and other precipitated proteins
what are 3 cellular pathologies in huntingtons
inclusion bodies
excitotoxicity
impaired BDNF
where are inclusion bodies found in HD
only in neurons
what cells die in HD and what are spared
medium spiny neurons dies
glia are spared
what happens when there is expression of mHTT in astrocytes
decreased expression of EAAT2
- more synaptic glutamate that overflows from the synapse
- neuronal cell death due to excitotoxicity
what does continued depolarization of a neuron lead to
increased intracellular calcium
what is the only approved drug for HD
VMAT2 inhibitor
(inhibits the loading of dopamine into synaptic vesicles)
what is the mouse model for HD
mice expressing mHTT clasp their hind feet and have striatal atrophy, motor impairments, and inclusion bodies containing mHTT protein
also show signs of depression and spatial memory loss
depletion of htt gene is embryonically
what is declarative memory
memories that can be brought to consciousness and expressed as remembered events
(daily events, words and meanings, history)
which type of memory involves the hippocampus
declarative
what is nondeclarative memory
procedural or implicit
memory that is acquired and retrieved unconsciously
(motor skills, associations, priming cues)
what brain areas support declarative memory formation
hippocampus and its subcortical connections to mammillary bodies and dorsal thalamus
where are declarative memories stored
distributed throughout cortical - medio-temporal lobe network
how are declarative memories retrieved
via the entorhinal cortex and processed by hippocampal formation
what is the hippocampal circuit affected by
inputs from amygdala, adding emotional aspect to memory
what kind of amnesia will occur with damage to the hippocampus or entorhinal cortex
anterograde
(inability to form new memories but old memories remain intact)
what brain areas are involved in nondeclarative memories
basal ganglia
prefrontal cortex
amygdala
sensory association corticies
cerebellum
NOT medial temporal lobe or midline diencephalon
what kind of memories are likely stored in the basal ganglia
motor related memories and learning
what is the morris water maze
tub of water with a platform underwater so mouse cannot see it
mice with normal hippocampus learn where platform is
mice with lesioned hippocampus do not learn where platform is
what are four different kinds of dementia
alzheimers
vascular
lewy body
frontotemporal
what is vascular dementia
sudden onset with variable symptoms from a stroke
what is frontotemporal dementia
primarily affects frontal lobe (atrophy of frontal lobe) so more cognitive symptoms
group of neurologic disorders associated with changes in personality, behavior, language, movement
gene pathology involves C9orf72 gene
what is lewi body dementia
progressive disease that causes hallucinations, decline in mental abilities, rigid muscles, slow movements, tremors
no hippocampal atrophy
what is the preclinical phase of alzheimers
minimal behavioral symptoms but pathological changes are occurring in cells
what is the mild cognitive impairment phase of alzheimers
neurological symptoms become apparent
low levels of Abeta and high levels of tau in CSF
plaques apparent but not correlated with degree of impairement
what is the dementia stage of alzheimers
profound neurological symptoms and rapid decline
neurofibrillary tangles become apparent
symptoms not associated with increase in plaque burden
what are two proteins involved in alzheimers pathology
phosphorylated tau form neurofibrillary tangles inside the cell
amyloid beta forms plaques outside the cells
where is phosphorylated tau and amyloid beta detected
both detected in CSF
phosphorylated tau can be detected in blood as well
where is the most prominent structural change in alzheimers
atrophy in temporal lobe
vascular changes
breaches of BBB
plaques, tangles, neuronal death, gliosis
what is amyloid precursor protein (APP)
transmembrane glycoprotein found in many different cell types
how is APP degraded
enzymes called secretases
what happens to APP in the non-pathogenic pathway
APP is cleaved by alpha and gamma secretases and the resulting fragments are soluble and can be cleared easily
what happens to APP in the pathogenic pathway
APP is cleaved by beta (not alpha) and gamma secretases resulting in a fragment called amyloid beta that has a tendency to aggregate and cause extracellular plaques
what are presenilins
subunits of gamma secretases
what is beta secretase also called
beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) because it initiated production of the toxic amyloid beta that plays a part in early alzheimers disease
what are two mutations that are sufficient to cause AD
amyloid precursor protein (APP) mutation
pre-senilin-1 and pre-senilin-2 mutation account for most cases of familial early onset AD
what is notch signaling
cleaved by gamma secretase and is important in adult nervous system for learning and memory
what are Abeta plaques surrounded with
Abeta oligomers that are in equilibrium with the plaques
- act as storage sites for Abeta oligomers
what can Abeta plaques do
disrupt synaptic activity
activated microglia and trigger inflammation
deposit on blood vessels increasing the risk of hemorrhage
what are neurofibrillary tangles
tau is hyper-phosphorylated and polymerizes forming twisted strands called neurofibrillary tangles
what do neurofibrillary tangles cause
they no longer bind to tubulin so they disrupt all intracellular transport including transport along axons and dendrites
what is the location difference between tangles and plaques
tangles: intracellular
plaques: extracellular
what are tauopathies
class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions
(FTD, AD, parkinsons)
some are a result of mutations in the tau gene
how do microglia interact with plaques
microglia surround plaques forming a protective barrier and clear away Abeta deposits by secreting substances that breakdown plaques
what glia can amyloid deposits activate
astrocytes and microglia
- microglia are initially beneficial because they mop up excess amyloid but as the disease progresses they become harmful as they release ROS that can activate neuronal apoptosis
what do plaques do to blood flow
reduce blood flow
compromise integrity of blood vessels and affect BBB
increased levels of Abeta seen in other organs (heart, muscles) as well
what is a specific mutation that increases AD risk
APOE 4
associated with increased risk and lower onset of AD
(APO 2 reduces risk)
what is the cholinergic hypothesis for AD
ACh is reduced at synapses in amygdala, hippocampus, and cortex of AD brains so cholinergic failure thought to underly AD symptoms
projections to cortex of presynaptic cholinergic neurons in NBM undergo profound degeneration in late AD
what are 4 drugs that are used as treatment for AD
- drugs that increase cholinergic activity
- NMDA receptor blocker
- antidepressants/psychotropic drugs reduce delusions and psychosis
- monoclonal antibodies against Abeta to remove plaques
what is a way that there can be early detection of amyloid plaques
retinal scans
what are antisense oligonucleotides (ASO)
DNA oligos with sequence complimentary to mRNA of a protein
- makes a mRNA-DNA hybrid
- mRNA destroyed by RNAse
- no protein synthesis
ASO spans splice sites to allow inclusion or exclusion of an exon that would have not normally been included
what are two types of inhibitory RNAs
siRNA
microRNA
what are the phases of a clinical trial
preclinical validation in animal models
phase 0: pilot studies
phase 1: studies of drug safety in patients or volunteers
phase 2: studies of drug efficacy
phase 3: studies of broader applicability of effect
drug/device approval
phase 4: postmarketing analysis for interaction with other drugs and long term effects
what are the inputs of the basal ganglia
inputs to striatum (caudate/putamen) is from entire cortex but caudate has more multimodal inputs than putamen
substantia nigra pars compacta
what are the outputs of the basal ganglia
from substantia nigra and globus pallidus
globus pallidus –> thalamus –> motor cortex
what is the main function of the indirect pathway
reduce unwanted movements (reduces firing of neurons that are not part of the direct pathway)
what is the primary problem in huntintons disease
degeneration of the neurons in the striatum and release less GABA
direct pathway is unaffected
what is the pathway for saccadic eye movement
- D1 receptors activate the caudate/putamen
- Caudate releases more GABA so more inhibition on the substantia nigra
- Since the substantia nigra is tonically firing, the inhibition from the caudate will cause the substantia nigra to release less GABA on the superior colliculus, activating the superior colliculus
- The superior colliculus has an excitatory effect on the gaze centers and eye movement, causing eye movement to occur
what is the pathway for movement through the direct pathway
- Cerebral cortex or the D1 receptors have excitatory input on the caudate/putamen
- Caudate/putamen releases GABA onto the globus pallidus internal inhibiting it
- Since the globus pallidus is tonically active, inhibition of it causes there to be less GABA released onto the thalamus
- Less GABA onto the thalamus causes it to be disinhibited, which activated the frontal cortex, causing movement
what does D2 receptor activation do to the indirect pathway
causes more movement
1. D2 receptors are activated which inhibit the caudate/putamen
2. Inhibition of the caudate causes less GABA to be released on the globus pallidus external
3. Less inhibition of the globus pallidus external causes there to be more GABA released onto the subthalamic nucleus since it is tonically firing
4. More inhibition of the subthalamic nucleus causes there to be less excitation of the globus pallidus internal
5. Less excitation of the globus pallidus internal means there is less inhibition of the thalamus
6. Disinhibition of thalamus leads to movement
