PHSYL 372 Motor Disorders

imported from hannah-mukuhi on quizlet

What is myasthenia gravis (MG)

immune system attacks AChR receptor of neuromuscular junctions with antibodies

Cause of MG

- unknown

- may be bacterial or viral infection

What is a distinctive symptom of Myasthenia Gravis (MG) that involves the eyelid?

Ptosis: drooping of eyelid due to ocular muscles being affected

What is a distinctive symptom of Myasthenia Gravis (MG) that affects the mouth?

Mouth hanging

What is a distinctive facial expression associated with Myasthenia Gravis (MG)?

Snarling smile

What respiratory symptom can occur in Myasthenia Gravis (MG)?

Dyspnea due to weakness of respiratory muscles

Treatment of MG

- remove thymus

- immunosuppressants

- anticholinesterase drugs

Why is it thought that MG is caused by bacteria or viral infection

herpes simplex has same sequence as Ach receptor

Immune response that causes MG

- T and B cells destroy herpes virus

- mistake Ach receptor as herpes

- begin autoimmune attack

Which muscles' Ach receptors are affected first

Muscles that control eye lids

Role of MG antibodies in endocytosis

Ach receptors that are bound to antibodies have a higher endocytosis rate than those not bound

How was it determined that MG was an autoimmune disease

- injected antigen of Ach receptor from fish into mouse in hopes that the mouse immune system will develop antibodies for it

- the antibodies will be later tagged with fluorescent molecules and visualized

- however fish receptor was close enough to mouse that mouse antibodies started attacking its own receptors

What type of antibody is rituximab?

Designer monoclonal antibody

What does rituximab target in the treatment of MG?

B cells in intermediate stages

How does rituximab help in Myasthenia Gravis (MG)?

It helps to stop the attack on acetylcholine receptors.

Which types of B cells does rituximab not target?

Immature or plasma B cells

What should patients be cautious about while on rituximab?

They should be careful not to catch new infections.

What does a neuromuscular junction look like?

What is neostigmine

anti-cholinesterase drug that reduces ACh-esterase activity preventing breakdown of Ach

Why does neostigmine mechanism of action work

Ach levels are elevated therefore higher probability of binding untargeted Ach receptors

Why is neostigmine useful as medicine?

It is reversible and needs to be taken daily

What is multiple sclerosis (MS)

immune system attacks myelin and associated oligodendrocytes, in late stages axons with no myelin die

Cause of MS

- unknown

- only people with epstein-Barr virus get MS

Distinctive symptoms of MS

scars near vessels in BBB causing breakdown and invasion of B and T cells

• Cognition affected in 50% of MS patients

Stages of MS

1. gradual decline in myelination and increase in deficits

2. symptoms flare up with periods of relief in between

Treatment of MS

- corticosteroid to suppress immune system

- rituximab

Consequence of demyelination in neurons

conduction of AP is impaired

How does current regulation work in myelinated neurons?

Current is kept from one node of Ranvier to the next.

What happens to current in demyelinated regions of neurons?

The current is lost through the membrane.

What happens after years of demyelination

axons upregulate Na channels however cannot cope with increased metabolic load and die

What is the animal model of MS?

Inject myelin proteins or CNS tissue together with agents that stimulate the immune system

• Treatment: Immunosuppressants, but not effective in halting disease

What is Guillain-Barre syndrome

immune system attacks Schwann cell myelin in PNS via polyclonal antibodies

Symptom of Guillain-Barre syndrome

- motor and sensory neuropathy

- can lead to paralysis depending on severity

• progresses from distal extremities first (unlike MG)

How does Guillain-Barre syndrome progress in body

- affects distal extremities first and other muscles later

- longer axons are more vulnerable

Cause of Guillain-Barre syndrome

follows EBV or mononucleosis infection

Treatment of Guillain-Barre syndrome

- suppress immune system

- intravenous rituximab

- support breathing

- disease often resolves by itself

Consequence of myelin sheath loss in Guillain-Barre syndrome

impairs nerve transmission

What happens after Guillain-Barre syndrome is resolved

myelin and nerve damage is spontaneously repaired

What is a motor unit

A motor neuron and all of the muscle fibers it innervates

• Motor neurons are huge so they use lots of ATP

• Use sustained Ca currents and Ca activated K currents to slowly pace firing to match muscle properties

  • Poor Ca buffering

Types of motor units

- eye muscle: 1:1 muscle/nerve ratio

- biceps: 750:1 muscle/nerve ratio

What is amyotrophic lateral sclerosis (ALS)

motoneuron death

• widespread mitochondrial damage

Cause of ALS

• uncertain

• possibilities:

  • toxins

  • trauma

  • oxidative tress and SOD1 mutation

  • calcium exitotxicity

Symptoms of ALS

- muscle weakness

- spasms

- paralysis

• frontotemporal dementia

Distinctive characteristic of ALS

mislocalization TDP 43 from nucleus to cytoplasm

Types of ALS

- sporadic

- familial

Role of TDP 43

- transcriptional repression

- RNA splicing

- mRNA transport

- microRNA maturation

What happens when TDP 43 migrates to cytoplasm

disrupts RNA processing and leads to cell death

Function of SOD1 enzyme

protects mitochondrial cells from ROS species

What does SOD1 mutation lead to

leads to SOD1 aggregates, oxidative stress and mitochondrial damage

Relationship of SOD1 with ALS

single mutated SOD1 gene or enzyme dysfunction causes ALS

What happens to Ca in ALS

ALS causes inadequate Ca buffering in large neurons

How does ALS lead to Ca toxicity

Ca channels and glutamate elevate Ca currents leading to high intracellular Ca which causes ROS development leading to excitotoxicity

What are some possible origins of sporadic ALS? (insane card, probably don’t worry)

• Toxic event triggers excess glutamate receptor activity, and Ca toxicity via NMDA and AMPA receptors, and Ca channels

• Poor fast Ca buffering (like parvalbumin) in motoneurons leads to toxic damage to mitochondria, which take up excess Ca, and this leads to release of reactive oxidative species (ROS, O2-) and lack of ATP, and eventually apoptosis via mPTP and caspase

• Excess Ca also activates calpain indiscriminately, which are the ‘scissors’ of cells, chopping proteins. This damages channels, transporters, glutamate uptake, all of which amplify Ca toxicity

• ADAR2 that edits RNA is also damaged, leading to more constitutively active AMPA and Ca channels

• Proteins like TDP43 get mislocalized to cytoplasm because of damage to nuclear transport and protein tagging, due to ROS and calpain

• Lack of ATP prevents proteosomes from pulling apart and destroying misfolded proteins

• Misfolded proteins clog up the cytoplasm in clumps, and calpain chops these clumps up into bits that seed other healthy proteins to misfold in prion-like way

• TDP43 and SOD1 aggregates (clumps) are released at synapses or via exosomes to spread misfolded proteins to nearby cells, and lead to a prion-like spread of misfolded proteins that eventually causes death

Potential Treatments for ALS

- Riluzole: a sodium channel blocker

- tofersen: antisense oligonucleotide of SOD1 mRNA reducing SOD1 protein synthesis

What is hSOD1?

Potential cure for familial ALS that involves viral injections that block mutant SOD1 or TDP43 gene actions

What type of disease is spinal muscular atrophy (SMA)

autosomal recessive disease

What causes SMA

genetic defect in SMN1 gene → loss of function mutation

Function of SMN1

development of motoneurons

What does genetic defect of SMN1 lead to

diminished abundance of proteins resulting in death of motoneurons in ventral horn

What is the most common cause of infant death?

SMA

Symptoms of SMA

- weakened muscle tone in limb and trunk

- respiratory problems leading to impaired breathing

- scoliosis

- difficulty walking and sitting due to feeble movement of arm and legs

- swallowing difficulties due to weak sucking reflex

5 physical symptoms to diagnose SMA

– poor muscle tone in the limbs and trunk

– feeble movements of the arms and legs

– swallowing difficulties

– a weak sucking reflex

– impaired breathing

Describe type 1 SMA

- called werdnig-hoffman disease

- most severe

- children never move or breathe independently

• 60% of all SMA patients

Describe type 2 SMA

- resp and feeding not as severe as type 1

- can sit but not walk

- can live into adulthood

- happens before 18 months

Describe type 3 SMA

- called kugelber-welander or juvenile SMA

- happens between 18 months and adulthood

- difficulty walking, muscle weakness, prone to infections

- can live into adulthood

Describe type 4 SMA

- adult form - less common

- affect walking

- symptoms emerge after 35

What decreases severity of SMA

if backup genes like SMN2 is present

Drawback of SMN2 gene

makes truncated ineffective SMN

How to make SMN2 more effective

- use antisense oligonucleotides to alter pre-mRNA splicing to make full length SMN proteins

- use virus to deliver replacement of SMN1 gene

Example of SMN2 antisense oligonucleotides

Nusinersen

What is Duchenne muscular dystrophy

- muscle wasting

- defect in dystrophin gene on X chromosome that causes loss of function

Cause of duchenne muscular dystrophy

Genetic origin → defect in dystrophin gene (loss of function)

Function of dystrophin

creates link between contractile machinery and extracellular matrix

Symptoms of Duchenne Muscular Dystrophy

- child does not run

- pseudohypertrophy

- in wheel chair by 12

• no treatment

How to detect Duschenne Muscular Dystrophy

genetic studies performed during pregnancy

What is EMG

extracellular recording of action potentials travelling down muscle fibres

EMG diagnostic criteria for difference diseases

What caused increased incidence of ALS among native Guamanians

eating bats infested with BMAA toxin that was created by cyanobacteria in cycad seeds