Nervous System Ageing LT2 Flashcards
What causes ALS and what are the susceptible neurones?
TDP-43 inclusions
Upper and lower motor neurones
What are the two descending spinal tracts and what do they control?
Lateral pathway = voluntary movement of distal muscle
Under direct cortical control
Ventromedial pathway = control of posture and locomation
Under brain stem control
What phases can voluntary movement be divided into?
Planning
Initiation
Execution
What is the role of sensory feedback?
Allows brain to correct for any deviation between the planned movement and actual movement
What is Lou Gehig’s disease?
Aka amyotrophic lateral sclerosis (ALS) = motor neurone disease
Causes loss of muscle control but sensory information is INTACT
What are the clinical signs of ALS?
Paralysis without loss of sensation of the upper limb
Accompanied by rapid wasting of muscle
Spasmodic rigidity of muscle results in permanent deformation of limbs
Speech and swallowing difficulties
Die due to respiratory issues = breathing nerves and muscles are affected
What were the pathological/anatomical findings?
Symmetric sclerosis (harderining) of lateral columns in spinal cord
In grey matter, only small number of cells left with deformed and atrophied cells
Muscle atrophy = amyotrophy
How are ALS clinical signs and pathological finding connected?
Grey matter motor nuclei are damage = weakness associated with muscular atrophy in body areas supplied by those cells
When white lateral column damage occurs = weakness associated with progressive contractures and spasticity
When does ALS onset?
Adult-onset neurodegenerative disease = 45-60 y.o
What genetic mutations cause ALS pathogenesis?
SOD1
Inclusion in sporadic ALS = TDP-43
Mutations in FUS
How is ALS passed on?
90% appear as sporadic mutations
10% is due to familial history
Transmits DOMINANT fashion = one copy is enough to cause ALS in humans
What type of mutation in SOD1 causes ALS?
Gain of function of the mutated protein causes aggregation
Not loss of enzymatic activity of SOD1
Where are these SOD1 mutations found?
In multiple cell types that contribute to SOD1-mediated ALS
Does neurone-specific expression of mutant SOD1 produce ALS-like phenotype?
No, neurone-specific expression of ALS-associated mutant human SOD1 may not be sufficient for development of the disease in mice
Mice expressing mutant SOD1 in all tissue developed ALS-like phenotype
How did they get neurone-specific expression of mutant SOD1 in mice?
Used a neurofilament promoter = only expressed in neurofilaments
In combination with Cre/LoxP
What were the 3 approaches to studying SOD1 mutations in difference cell types?
Try expressing mutation in only one type of cell
Express mutation in all cells and remove expression from one cell type at a time
Co-culture expt = reconstruct interaction between the two
What are the different cell types SOD1 is found in, in the brain?
Motor neurones
Astrocytes
Microglia
Schwann cells
What time in the progression does mutant SOD1 in motor neurones drive?
Early disease progression
What role do motor neurones play in ALS?
Most likely, motor neurones are important for disease initiation
What time in the progression does mutant SOD1 in microglia drive?
Late disease progression
We can see when the mutated SOD1 is removed from microglia in the late disease phase mice lived 75days longer
What time in the progression does mutant SOD1 in astrocytes drive?
Late disease progression
Less severe difference in survival compared to microglia only 48 days instead of 75 in late phase
How are induced pluripotent stem cells (iPSCs) made?
Study genes important for stem cell funciton
When 4 such genes were transfered into cells taken from the skin = reprogrammed into PSCs
These PSCs could develop into all cell types of an adult mouse = iPSC
What causes ALS clinical hallmarks?
The death of motor neurones causes paralysis and muscle atrophy
What was the difference between removing mutant SOD1 from motor neurones compared to microglia?
Removal of the SOD1 transgene from motor neurons was found to substantially delay but not halt the onset of disease.
While removal of the mutant SOD1 transgene from microglia was found to extend life span in the animals by prolonging the disease’s symptomatic phase
How did they test whether the human spinal motor neurons produced from ESCs were useful for investigating disease processes?
Tested whether they were sensitive to the toxic effect of glial cells overexpressing a mutant SOD1 gene product
What was seen when SOD1-mutant and WT glial cells were cocultured with transgenic human motor neurones?
In cultures containing SOD1G93A glia, there were less than half as many motor neurons (131± 53, n = 3) as in cultures containing nontransgenic control glia (269 ± 44, n = 3)
The deficit in motor neuron survival in cocultures with SOD1G93A glia became even more pronounced after 20 days.
A similar effect on survival of human ESC-derived motor neurons was observed when they were cultured for 20 days with media conditioned by SOD1G93A glia
What causes the toxic effect of glia on motor neurones?
The action of the mutant SOD1 protein
NOT the overexpression of the SOD1 protein (large-scale protein aggregation)
What does SOD1 mutation in Schwann cells do to ALS progression?
SLOWS disease progression
What does SOD1 mutation in muscle and vasculature do to ALS progression?
No effect on disease
Vasculature is damaged early in ALS = leading to loss of tight junctions between ECs and microhemorrahges
But this may not be from mutant SOD1 in pericytes
How does excitotoxicity contribute to SOD-1 mediated ALS?
Exocitotoxicity = hyperactivation of motor neurones
Resulting from failure to rapidly remove NT glutamate from synapse due to deficiency in glutamate transporter in neighbouring astrocytes
How does ER stress contribute to SOD-1 mediated ALS?
Er stress = induced by abnormal interactions of mutant SOD1 with ER proteins
How does proteasome inhibition contribute to SOD-1 mediated ALS?
Proteasome inhibition = due to overload of proteasome degradation pathway
Overloaded with ubiquitinated misfolded protein aggregates may damage astrocytes and motor neurones
How does mitochodnrial dysfunction contribute to SOD-1 mediated ALS?
Provokes release of cytochrome c in motor neurones, which triggers apoptotic pathways
Astrocytes leads to nitroxidative stress; they are less susceptible to apoptosis compared to neurons
How does toxic extracellular SOD1 mutation contribute to SOD-1 mediated ALS?***
Is secreted from motor neurones and astrocytes after interaction with components of neurosecretory vesicles
How does superoxide production contribute to SOD-1 mediated ALS?
Produced from microglia or astrocytes = can damage neibouring motor neurones
How does altered axonal transport contribute to SOD-1 mediated ALS?
Includes an increase in retrogradely transported stress-related proteins
Reported in mutant SOD1-expressing motor neurones
How does synaptic vesicle defects contribute to SOD-1 mediated ALS?
Such as stalling and loss from distal synapse in vulnerable motor neurones is early event in ALS
How does loss of tight junction proteins contribute to SOD-1 mediated ALS?
Results in distribution of blood-spinal cord barrier and occurrence of microhemorrhages within spinal cord well before disease onset
Name a potential therapy to extend survival in ALS patients?
Silencing mutant SOD1 using RNAi to protect against neurodegeneration and extend survival of ALS model
Explain how antisense oligonucleotides (ASOs) therapy for SOD1 in humans will help ALS?
It reduces SOD1 by binding to mRNA and preventing SOD1 translation into protein
It was found the removal of SOD1 WT didn’t have an adverse affect
Explain how stimulation of neurogenesis in regions of injury may contirbute to restoring functions in humans with ALS?
Explain how transplantation of glia precursor cells protect against ALS?
