Motor Neuron Disease/Amyotrophic Lateral Sclerosis (ALS) PART I Flashcards
Define Motor Neuron Disease/ Amyotrophic Lateral Sclerosis (ALS)
Chronic neurodegenerative condition causing
muscle wasting, paralysis and death usually
within 3-5 years due to respiratory failure
Neuropathological features of ALS?
- Amyotrophy
- scarring of the corticospinal tracts
Compare ALS risk in men vs women
Greater in men
Specific targets of ALS?
Upper motor neurons and Lower motor neurons
What makes UMN and LMN vulnerable to ALS severe symptoms?
- Both have long axons (length / cell diameter ~10,000) - Very active - High energy demands
Briefly describe the outcomes of UMN and LMN pathology in ALS
UMN -> spasticity
LMN -> atrophy
Describe the features of ALS symptoms
- progressive denervation + secondary muscle weakness of limbs, trunk, tongue, resp (intercostal) muscles
- Impaired speech & swallowing (bulbar signs)
- Spastic weakness + paralysis in almost all skeletal muscle
- NO impairment of bladder/bowel/sexual function
- SPARED occulomotor/sensory/autonomic function
{NB: cognitive function affected in a minority of cases]
Describe the onset and progression of ALS
Starts focally and spreads
Usually starts in distal muscles of limb/bulbar and then spreads
Specific examples of early ALS symptoms
- Wasting of thenar eminenence
- Wasting of the tongue (bulbar)
Early diagnostic tests for ALS (and positive results)?
- Muscle biopsy -(stain for ATPase)-> atrophic fibres
- Electromyogram (nerve conduction test) -> impaired conduction (and compensatory mechanism)
How do motor units compensate for the effects of ALS
Sprouting of neighbouring axons from neighbouring motor units (collateral branches)
How to distinguish ALS from other motor neurone diseases?
Presence of both upper and lower motor neurone signs
Examples of LMN signs?
Muscle weakness, wasting, fasciculations, cramps
Examples of UMN signs?
Stiffness, slowness of movement, slow and clumsy speech, Babinski
What could bulbar symptoms indicate in the context of ALS?
(i.e. UMN and LMN)
Progressive bulbar palsy
Describe Primary Lateral Sclerosis (PLS)
Effects on UMNs predominate:
- spasticity
- hyperreflexia
{20 yr survival)
Features of an MRI of pt with ALS (PLS)
- Wide precentral sulcus
- Atrophy of adjacent gyri
Give an overview of the treatment of ALS
speech & swallowing- speech therapist
mobility around home- occupational therapist
swallowing & feeding- NG tube or PEG
breathing- oxygen, assisted ventilation
slowing disease progression- Riluzole (extends survival ~3 months_
Sites targeted in ALS?
- motor cortex (UMN)
- brainstem (LMN)
- spinal cord (LMN)
Histological features of ALS?
Ubiquinated inclusion in neuronal cell bodies and proximal axons
What is an ubiquitinated protein?
Post-translational modification by a small 76 amino acid regulatory protein, ubiquitin
Substrate designated for degradation is tagged w/ ubiquitin. This is recognised by proteosome, which carries out this process.
Ubiquitinated proteins are characteristic of what conditions?
ALS (sporadic & familial) and a subset of fronto-temporal dementia
Two forms of ubiquitinated inclusions?
- filamentous
- compact
What protein is a major component of ubiquitinated inclusions (in SALS/FALS/FTLD)?
TDP-43
What proportion of ALS cases are familial?
10%
What is the molecular mechanisms that have been identified in ALS?
Abnormalities in:
- RNA binding proteins
- proteostasis
(- cytoskeletal proteins)
Gene pathways involved in FALS?
- RNA processing]- (TDP-43, FUS)
- protein quality control (“waste disposal”)]- (VAPB, P4HB, SOD1, VCP, ubiquitin2, P62, OPTN
- excitotoxicity]- DAO
What gene encodes for TDP-43?
TARDBP (TAR DNA binding protein)
NB: TAR = Trans activating response
Describe the actions of TARDBP
TARDBP encodes TDP-43
Binds TAR DNA sequences in DNA/RNA, acting as a transcriptional repressor
i.e. inhibits splicing and regulates mRNA transport/local translation
Sites possibly responsible for TDP-43 and FUS mislocalisation?
- Nuclear localisation signal (enable protein to be taken into nucleus)]- FUS
- Nuclear export signal (enable protein to leave nucleus -> cytoplasm)]- (Importin is the nuclear transport protein)
Difference in TDP-43 staining in healthy people and ALS patients
TDP-43 appears in cell nuclei in healthy people
TDP-43 is located in the cytoplasm in ALS patients
Effect of TDP-43 mutation in animal models?
Neurodegeneration (cortical and spinal neurons) but not consistent forming of inclusions (present in both wild-type and mutant rodents)
What genetic changes are found in FALS and FTLD?
FUS positive inclusions
What is FUS/TLS?
FUS: fused in sarcoma
TLS: translocation in liposarcoma
What process is TARDBP and FUS both involved in?
Regulation of RNA processing
Effects of TDP-43 on transcription and mRNA splicing?
Transcriptional repressor
Exon skipping (binds to CFTR pre-mRNA UG intronic tract)
Effects of FUS on transcription and mRNA splicing?
Transcriptional activator
Part of spliceosome machinery
Main target of action for TDP-43 and FUS
Introns
Describe the cytoplasmic stress granule response
Aims to conserves mRNAs during cell stress
Activity + cell stress stimulate nuclear efflux of TDP-43 and FUS to the cytoplasm, where they are withing RNA transport granules (stress granules and processing bodies)
Effects of TDP-43 and FUS knockout on dendrites?
TDP-43 KO: reduced dendritic branching/ synapse formation
FUS KO: reduced spine formation
NB: TDP-43 regulates local protein synthesis on dendrites
What causes TDP-43 mislocalisation?
Inhibition of TDP-43 nuclear transport protein (importin) -> accumulation of soluble TDP-43 in cytoplasm
NB: NLS is NOT affected in TDP-43
What causes FUS mislocalisation?
mutation of nuclear localisation signal-NLS
[Experimental evidence]
Inhibition of FUS nuclear transport protein (transportin) -> FUS accumulation in cytoplasm
Pathogenesis of SALS?
[nuclear transport proteins decrease w/ age -> increased cytoplasmic TDP-43]
- cell stress/oxid. stress/heat shock/ER stress acts as the trigger
- > stress granules in cytoplasm that contain housekeeping mRNAs that don’t require translation during stress also contain FUS and TDP-43
[NB: these stress granules could act as precursors for large inclusions]
Relation of TDP-43 inclusions to ALS cases
Common to 97% of ALS cases (SALS and FALS)
Exceptions are FALS cases w/ FUS mutations (0.5% of ALS cases) and SOD1 (2% of ALS cases)
Outcome of TDP-43 knock out in embryos?
Lethal
Outcome of partial/conditional TDP-43 knockouts?
Motor neuron defects
Progressive motor phenotype
Outcome of selective knockout of TDP-43 in glia/muscle
ALS-like phenotypes
