ALS Flashcards
What are key symptoms in ALS?
Bulbar signs: Impaired speech, swallowing and wasting of toungue muscle.
Dennervation and weakness of limbs, tongue, respiratory intercostals.
Spastic weakness and paralysis affecting almost all skeletal muscle.
Respiratory failure
No impairment of bladder, bowel or sexual dysfunction.
Oculomotor, sensory and autonomic function spread
Cognitive function may be affected in minority of cases.
What are the diagnostic tests?
Muscle biopsy and electromyogram
Muscle stained with ATPase shows grouped atrophic fibres.
What are the differences between upper and lower motor neuron signs, and what about primary lateral sclerosis?
LMNs: Muscle weakness, wasting, fasciculations, cramps
UMNs: Stiffness and slowness of movement, slow and clumsy speech, Babinski signs often present.
PLS: Predominant effects on UMNs, causing spasticity and hyperreflexia.
What is the treatment for ALS?
No cure. Speech and swallowing therapy. Mobility- occupational therapist. Physiotherapy Mental health support Breathing- oxygen, assisted ventilation Cramp/Spasm treatment. Slowing disease progression (Riluzole, 3 months)
What is the neuropathology of ALS?
Motor neuron loss in spinal cord, brain stem, motor cortex
Corticospinal tract degeneration
Ubiquitinated inclusions in neuronal cell bodies and proximal axons.
TDP-43: 97% of ALS cases and 50% of FTD have TDP-43 (+ve) ubiquitinated inclusions.
From highest to lowest prevalence, list the genetic mutations in FALS.
(CSTF: Can stephen throw far? [no])
c9ORF72- chromosome 9 reading frame 72.
SOD1 (superoxide dismutase 1)
TARDBP
FUS
What areas are affected by FALS mutations?
RNA binding proteins- TARDBP, FUS
Protein control- VCP, UBQLN2, SQSTM1, p62, OPTN, c9orf72, PDI
Excitotoxicity- DAO
Describe the RNA binding proteins and what happens in mutation.
What is the pathogenic process?
TARDBP encodes TDP-43, which binds TAR DNA seuqqnces in DNA/RNA and acts as a transcriptional repressor- inhibits splicing of RNA and so regulates mRNA transport/local translation.
Mutated TDP-43 is cleaved and localises to cytoplasm- in motor neurons, glia and neurites. It is hyperphosphorylated, ubiquitinated. This can cause neurodegeneration (transgenic TDP-43 rodents produce paralysis and neurodegeneration).
FUS: This is a transcriptional activator. It is part of the spliceosome machinery.
Activity and cell stress stimulate nuclear efflux of TDP-43 & FUS to cytoplasm, where they are found in RNA transport granules. Cytoplasmic stress granule response conserves mRNAs during cell stress.
- Impaired RNA processing
- Formation of inclusions central to pathogenesis
- Is Mislocalisation of TDP-43 causal?
Inhibition of nuclear transporters for the proteins causes accumulation in cytoplasm. Transgenic mice with defective nuclear localisation have insoluble phosphorylated TDP-43 inclusions and are fucked. THEREFORE TRANSPORT INTO NUCLEUS IS KEY TO DISEASE.
How is C9ORF72 thought to be involved in FALS?
Most prevalent mutation.
LIkely to be member of DENN protein group involved in membrane fusion, trafficking, endo and exocytosis.
RNA foci accumulate in ALS.
Pathology includes inclusions that are TDP-43 negative, but p62 positive.
What 2 protein regulation pathways are FALS genes important in?
Protein unfolding
Protein degradation by autophagosome/proteasome
Which proteins are involved in UPR?
- VAPB
- PDI (protein disulphide isomerase)- ER foldase, needed for disulphide bridge formation.
Mutations in these cause ubiquitinated protein aggregates.
What proteins are involved in protein export to the proteasome?
SOD1: Binds to component of export system (Derlin 1)
VCP: Second stage, modified chain for ubiquitination
Ubiquilin 2: Binds to ubiquitin chains and guides it to the proteasome.
Which proteins are involved in autophagy, and which novel gene regulates them?
P62
OPTN (optoneurin)
Regulated by Tank binding kinase-1. (TBK1). This phosphorylates optoneurin and p62, facilitating optoneurin binding to phagosome, leading to autophagic turnover. Strengthens importance of autophagy in ALS pathogenesis.
What is the involvement of neurotoxicity?
Riluzole is anti epileptic, targets voltage dependent Na+ channels and reduces glutamate release.
NMDA activated by glutamate and D-serine. D-serine highly elevated in SALS.
High DAO needed to metabolise and regulate D-serine levels. When DAO is inactivated/mutated, this can cause FALS.
What are some treatment strategies?
Edaravone: Free radical scavenger. No effect on severe cases. Hint of an effect in a 100 patient study.
Therefore, Riluzole and Edaravone.
Targeted gene delivery or gene deletion with viral vectors can neutralise mutation effects. SOD1 gene delivery and crispr/cas9 being investigated.
