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