Neuromuscular pathology Flashcards
Neuromuscular anatomy:
what are muscles comprised of
where do motor neurones originate, and what do they innervate
Muscle composed of: fascicles, fibres and myofibrils
Primary motor neurons in ventral horn project to muscle targets where they form motor end plates on muscle fibres
One motor neuron innervates many fibres -together they are a motor unit
What are the main cytoskeletal proteins within muscle?
Actin
Filamin C
Dystrophin
Sarcoglycan complex
Dystroglycan complex
Laminin
Collagen ECM
Cytoskeletal proteins in muscle cells interaction
Sarcomere contains actin which is linked to the sarcoglycan complex in the cell membrane by filamin C and dystrophin.
Sarcoglycan complex is anchored in the collagen ECM as it is connected to dystroglycan complex in the cell membrane which laminin is binded to extracellularly
What are the different domains of dystrophin?
Actin-binding domain
Rod domain containing hinge regions
Cysteine rich domain
C-terminal domain
What tissues is dystrophin expressed in?
Muscle
Brain
What happens in MD?
Duchenne MD: nonsense or frameshift mutation causes production of non-functional protein
Becker MD: in-frame mutations lead to partially functional protein being produced, so less severe than DMD
What new treatments are being developed for MD?
Deliver functional dystrophin in a virus
Use anti-sense oligonucleotide to skip a mutated exon to restore the reading frame - produces protein slightly dysfunctional, but better than none (converts DMD > BMD)
Edit the genome - remove the mutated exon, or fix the mutation using CRISPR
What is required for motor neurons to stay alive in development?
Neurons need targets to stay alive - Innervation of muscle is required for neuronal survival
If limbs are removed, motor pool decreases if experimentally added, motor pool expands
How does innervation change throughout development?
Synaptic pruning
Motor neurons initially synapse with as many targets as possible, as development progresses, they are pruned back, synapses are lost with many targets
Allows for individual muscle fibres to be innervated by only one motor neuron
Occurs in muscle and ganglia and in brain - climbing fibres are pruned that innervate purkinje neurons in cerebellum
What is SMA?
Spinal muscular atrophy
LMN die during development which results in muscle atrophy which ultimately kills the patient
What causes SMA?
SMN1 mutation
Protein localised to nucleus and cytoplasm
Associated with RNA metabolism e.g. splicing, transport > and by extension cytoskeletal transport and dynamics
When SMN1 mutated, patients commonly only have 10% of SMN2 to fall back on
SMN genes in humans
Used for RNA metabolism, cytoskeletal transport
Humans have two SMN genes whose sequences nearly identical
SMN2 commonly mutated = 90% of the time exon spliced out
What determines the severity of SMA?
The copies of SMA2 genes
If they are mutated as well, each copy will only provide 10% production of the protein. If two copies are present = 20% etc.
The more copies of SMN2, the less severe the disease when SMN1 mutated
Where does most damage in SMA occur and why?
SMA genes are constitutively expressed, but RNA metabolism, processing and transport is particularly important in motor neurons due to their long axons
Motor neurons transmit mRNA for actin down to synapse to allow growth of neurone during development
Due to this increased need, it is LMN that die
Death of MN results in muscle atrophy which causes eventual death due to respiratory insufficiency
What markers can indicate SMA?
High levels from birth of neurofilament L in the blood are indicative of (but not specific to) SMA due to release of NfL when neurons are damaged or die
NfL is measurable in the blood in healthy adults due to Nf half lives, but in very low levels
