Motor Neuron Disease Flashcards
What are the 4 main types of MND?
Amyotrophic lateral sclerosis (ALS)
Progressive bulbar palsy (PBP)
Progressive muscular atrophy (PMA)
Primary lateral sclerosis (PLS)
Which MNs are affected in ALS?
Upper and lower
What are the symptoms of ALS?
Paralysis Limb weakness Difficulty keeping head upright Difficulty with speech and swallowing Breathing problems Emotional lability
Name the 2 licensed drugs for ALS
Riluzole
Edaravone
What is riluzole and what is its effect?
Anti-glutamatergic
Slightly increases survival
What is edaravone and what is its effect?
Free radical scavenger - decreases oxi stress
Positive trial data with limited patient sample
Which other disease do some ALS patients also have?
FTD
Which type of MNs are most vulnerable to death in ALS?
MNs under voluntary control
MNs innervating fast twitch muscles
Name 4 genes that cause familial ALS
SOD1
TDP-43
FUS
C9orf72
What is the role of TDP-43?
RNA binding protein
What is the role of FUS?
RNA binding protein
What is the role of SOD1?
Superoxide dismutase - converts superoxide to water/hydrogen peroxide
What is the overall way in which SOD1 mutation causes ALS?
Toxic gain-of-function
What might the SOD1 toxic gain-of-function involve?
Increased superoxide
Axonal transport
Where are TDP-43 and FUS normally located?
Nucleus
Where are TDP-43 and FUS located in ALS and what is the effect of this?
Cytoplasm
Form cytoplasmic inclusions - depleted from nucleus
What are the 2 proposed mechanisms for how mutant TDP-43 and FUS cause ALS?
Nuclear loss-of-function - transcription, splicing
Cytoplasmic gain-of-function - RNA transport
What are the 3 proposed mechanisms for how hexanucleotide repeat expanded C9orf72 cause FTD-ALS?
C9orf72 loss-of-function
RNA toxicity - RNA foci formation
Protein toxicity - RAN translation in HRE - forms toxic DPRs - aggregation-prone
What is thought to be the way in which mutant C9orf72 causes FTD-ALS?
RNA-mediated toxicity - gain-of-function
C9orf72 haploinsufficiency - loss-of-function
What could cause the heterogeneity seen in ALS survival times?
Mutations in ALS-causing/susceptibility genes
Environmental factors
Which environmental factors increase ALS risk?
Serious head trauma
Increased exercise
Heavy metal exposure
Low vitamin A diet
Mutations in which gene link ALS to poor blood supply and what is the physiological role of this gene?
ANG
Angiogenesis
Which pathogenic mechanisms are thought to be involved in ALS?
Protein aggregation Oxi stress Axonal transport defects Mito dysfunction Glutamate excitotoxicity RNA processing
How might protein aggregates lead to MN death in ALS?
Proteasome blockage
Autophagy overload
Depletion of essential cellular proteins - e.g. chaperones - increases misfolding - forms more aggregates
Toxicity leads to ER stress and axonal transport deficits
Which properties of MNs make them susceptible to excitotoxicity?
Low Ca2+ buffering capacity
High number of Ca2+-permeable AMPARs
What could be the effect of the deficits in anterograde and retrograde axonal transport seen in ALS model mice?
Key factors not taken to/from muscle
What is the evidence for the role of oxidative damage in ALS?
Increased oxidative damage in post-mortem ALS CNS tissue
How is mitochondrial function altered in ALS MNs?
Decreased ETC activity
Decreased mito membrane potential
Altered Ca2+ homeostasis
Where does mutant SOD1 localise to in ALS?
Spinal cord mitochondria
How might microglia be involved in ALS pathogenesis?
Become overactive when MNs die
Release ROS - toxic
Damage MNs - does not cause death
How are oligodendrocytes affected in SOD1 mutant mice and what is the effect of this?
Degenerate
Decreases support for MNs
What is the role of astrocytes in ALS pathogenesis?
Contribute to induction and propagation of MN death
What is the physiological role of astrocytes?
Modulate neuronal excitability - prevent excitotoxicity
Which patient characteristic prevents stratification in trials, making it more difficult to identify effective treatments?
Progression rate - varies between individuals
Name 2 potential ALS treatment types
ASOs
Stem cells
How might ASOs be used to treat ALS?
Prevent mutant gene expression - SOD1, C9orf72
How might stem cells be used to treat ALS?
Replace glial cells in spinal cord - increase MN support
Which mechanisms could future ALS treatments target?
Aggregation MN apoptosis Mitochondrial deficits Axonal transport Microglia
