ALS Flashcards
What is Amyotrophic Lateral Sclerosis?
Degeneration of UMNs and LMNs
Low excitable, fast-fatiguable fibres degenerate first
M>F
Age of onset 55
10% Familial
Sx: Muscle weakness, loss of voluntary movement
- Maintained cognitive function, bladder/bowel function
SOD1 mutations in ALS
Superoxide Dismutase 1 gene
- Toxic gain of function causes increased reactive oxygen species (hydrogen peroxidase) leading to neuronal death
- Lower levels of Excitatory Amino Acid Transporter 2 (EAAT2)
- Increased synaptic glutamate levels –> Ca2+ influx, and excitotoxicity
SOD1 animal models- most common
SOD1G93A: most common, onset at 90d/death at 120d
SOD1D83G: may be more representative
SOD1 example model
Nagai 2007
Growing primary spinal/Embryonic SC-derived MNs on SOD1-mutated astrocytes kills MNs, reducing axonal length and cell body diameter
- Release of astrocytic neurotoxic factors
- Myocytes, microglia and fibroblasts had no effect
Only affected MNs, with no effect on GABAergic/DRG neurons
Issues with SOD1 models
No development of Fronto-Temporal Dementia OR Substantial cortical MN degeneration (seen in humans)
Mutations are needed in both neurons and glia
Lack of correlation between human/animal studies
Minocycline treatment for ALS in SOD1 model
Demonstrated increased survival in SOD1 mouse models
BUT
Phase 3 RCT: Minocycline is determined harmful
- AEs more common in treatment group
- ALSFRS-R score deteriorated more quickly
TDP43 models of ALS
Mutations in the TARDP gene
- Aberrant RNA metabolism, leading to nuclear inclusions formation
Issues with TDP43 models
- M/F survival differences: may be underlied by myenteric plexus cell death
- Lack of symptomatic differences (grip strength, wire hanging) between males and females
- Differences in toxicity between WT/mutant overexpression
- Many animals die of other causes
- Needed in glia; neuronal-specific overexpression produces a rapidly progressive phenotype
- Astrocyte knockdown drives mass neuronal loss
- TDP43 inclusions are most abundant in oligodendrocytes in humans
VCP Mutant Models
VCP R155H Knock-in
- Develop ALS and Fronto-temporal dementia
- Cytoplasmic TDP43 accumulation in the SC
- Progressive muscle weakness
GluR2 expression in ALS
ALS MNs have reduced editing efficiency of GluRs vs. Purkinje cell controls
- absence of GluR2 subunit increases Ca2+ permeability –> excitotoxicity
Calcium buffering proteins in ALS
Remove excess intracellular calcium
- Are reduced in ALS/ SOD1 cell models
Gold standard ALS treatment
Riluzole
Improves long-term survival with early administration
Calcium binding proteins treatment for ALS
Cross-breeding SOD1 mutants with Parvalbumin o/e mice
- Increases neuronal survival and overall progress
- Human application
Calcium channel blockers treatment for ALS
e.g. Lomerizine
Efficacious at increasing MN survival in SOD1 model only
Neurotrophic factor treatment for ALS
Intrathecal GDNF/BDNF improves relative survival
- Clinical usage- no sig. benefits
- May differentially affect motoneurones
Heat Shock Response Manipulation
Arimoclomol
ALS patients have an upregulated heat shock response
Arimoclomol enhances neuroprotective effects by prolonging Hsf-1 activation
Increases expression of HSP70/90- reduces heat shock protein aggregation
-Treatment presymptomatically (AND symptomatically) improved motor neuron survival and increased hind limb muscle function
2018 DB RCT showed Arimoclomol was safe and well tolerated in SOD1 ALS patients, reducing ALSFRS-R score
iPSCs for ALS treatment- studies for
Kondo 2014: Glial-rich progenitors
- Increased pAKT activation and signalling
- Improved motor scores
- Surival higher in males
- BUT most cells differentiated into GFAP+ astrocytes
Clinical trials promising but multiple injection sites needed
Xu 2011: Intraspinal transplantation of rodent glial-restricted progenitors
- Promoted MN projection
- Delayed respiratory function
- Extended disease progression
iPSCs for ALS treatment- evidence against
ICV injections of MSCs
- Protects motor neurons, activating p-AKT signalling. switch from pro to anti-inflammatory pathways
- Does not delay disease onset or increase neuronal survival/grip strength
Insulin-Like Growth Factor 2 in specific ALS patients
iPSCs derived from ALS patients with specific mutations of motoneurons
ILGF2 is expressed at higher levels in less vulnerable neurons
-Vardenafil (increases IGF2 expression) differentially affects ALS patients depending upon their mutation status
Targetting endogenous SCs in ALS
Nicotine treatment enhances oligodendrocyte proliferation in an MS model
-Reduced GFAP+ cells and inflammation
Autonomic deficits in ALS
Sympathetic nerve activity/ BRS
Increased MSNA but lower IML neuron numbers
Increased BRS may be compensatory
