neuromuscular pathologies

• In Duchenne MD, a nonsense or frame-shift mutation causes production of truncated, non-functional protein. In Becker MD, in-frame mutations lead to a partially functional protein being produced, and so BMD is significantly less severe than DMD.
• a) deliver functional dystrophin in a virus (vector). Microdystrophin is a shortened version of the dystrophin protein. This modified form of dystrophin is engineered to be smaller in size while retaining essential functional elements to maintain structure and function of muscle fibres

  b) use an anti-sense oligonucleotide (a short RNA molecule) to skip a mutated exon to restore the reading frame (in-frame) so the protein is still a little functional

  c) edit the genome ( remove the mutated exon or fix the mutation using CRISPR
• During spinal cord development, motor neurons with common targets and afferent inputs cluster into discrete nuclei, termed motor pools.
• During development, innervation of muscles is required for neuronal survival. More neurons are born than are ever required, and any that do not innervate muscle die off. As such, if limbs are removed, then the motor pool decreases; if they are experimentally added, then it expands. 
• After neurons have made contact with muscles, the pattern of innervation also matures and undergoes ‘pruning’ such that axons that innervate multiple targets die back such that individual target fibres become innervated by single neurons.

  Synaptic pruning is a fundamental feature of nervous system development…
• example of pruning in the cerebellar purkinje fibres

  Climbing fibres in the cerebellum (see unit 14) innervate multiple Purkinje neurons, but then prune back to just a single target neuron.

  Climbing fibers convey error signals related to motor performance. They detect mismatches between intended and actual movements, Activation of climbing fibers is associated with a type of synaptic plasticity called long-term depression (LTD) at the synapses between climbing fibers and Purkinje cells. This process is thought to be crucial for motor learning and the refinement of motor coordination.
• synaptic pruning is also seen in the cerebral cortex across the prefrontal, motor, somatosensary, visual cortices and limbi systme
• ALS stands for Amyotrophic Lateral Sclerosis. It's a progressive and degenerative neurological disorder that affects the nerve cells responsible for controlling voluntary muscle movement - motor neurones.
• The disease usually progresses over time, leading to muscle weakness, atrophy, cramps, twitching, spasticity, and eventually, paralysis. other symptoms include: cognitive and behavioural impairment, dysphagia, dysarthria and difficulty breathing
• Diagnosing ALS can be challenging as there isn't a single test. It typically involves ruling out other conditions that mimic ALS symptoms. Tests such as electromyography (EMG), nerve conduction studies, MRI, and blood and urine tests might be performed to aid in diagnosis.
• Treatment: Currently, there's no cure for ALS. Treatment focuses on managing symptoms, providing supportive care, and improving the quality of life for individuals affected by the disease. Medications, physical therapy, assistive devices, respiratory support, and nutritional support are some of the strategies used to manage symptoms and provide support.
• ALS on a cellular level causes:

  • hyperexcitibility
  • glial dysfunction
  • Axonopathy
  • impaired protein homeostasis
  • impaired DNA repair
  • oxidative stress
• ALS~30 genes

  implicated but complex genetics; often no simple inheritance pattern and certainly an interaction with the environment.
• amyotrophic lateral sclerosis:

  • rapidly progressive neurodegenerative disorder of motor system
  • affect lower and upper motor neurones
  • affects: upper and lower limbs, bulbar and respiratory regions -> progresses to respiratory dysfunction and global muscle weakness
  • 3 main hypothesis : dying forward hypothesis, dying back hypothesis and the independent hypothesis
• TMS suggests cortical hyperexcitability as important to ALS pathogenesis so is being developed as a potential diagnostic biomarker for ALS.
• What happens when you have too much glutamate?

  Too much glutamate in the brain can cause nerve cells to become overexcited. Overexcitement can lead to brain cell damage and/or death. In this case, glutamate is called an excitotoxin.
• ALS pathophysiology mechanisms

  • altered RNA processing leading to prion-like self-aggregation
  • SOD1 mutations leading to free radical toxicity
  • cascading inflammatory responses
  • excessive concentrations of glutamate
  • The rarer entity of familial ALS has numerous genetic mechanisms, most frequently repeat expansion of the C9ORF72 gene and various mutations of the SOD1 gene.
  • Mutated SOD1 protein misfolds and forms aggregates, leading to cellular injury and eventually apoptosis. Both genetic aberrations are inherited in a mainly autosomal dominant pattern.
• ALS pathophysiology

  • degeneration and gliosis of axons within the anterior and lateral columns of the spinal cord
  • Motor neurons within the spinal cord anterior horns and Betz cells within the motor cortex are also lost
  • Unique to amyotrophic lateral sclerosis, Bunina bodies are eosinophilic inclusions visible in affected motor cells in many cases
  • Intracellular TDP-43 inclusions are present in most cases, providing a pathologic link between ALS and frontotemporal dementia (FTD), in which they are also found
• what is this?

  bunina bodies - small eosinophilic intraneuronal inclusions in the remaining lower motor neurons, hallmark to ALS