General mechanisms in neurodegeneration Flashcards
what defines a neurodegenerative disorder
damage on different brain regions where occlusions are localised.
What do occlusions consists out of?
aggregates.
what are aggregates
misfolded, clustered (hydrophobic beta sheets) proteins
what can aggregates lead to?
- loss of function phenotype
2. gain of toxic function
how are aggregates controlled
protein quality control
where does protein synthesis take place
proteins are synthesised in the cytosol and the ER
cytosol: proteins that are packed to be transported
ER: proteins that are soluble
what proteins prevent the binding of misfolding proteins?
chaperones (heat-shock proteins)
how do HSP/chaperones prevent misfolded protein binding?
chaperones facilitate protein folding and refolding by keeping proteins in “a folding-competent state”
which chaperone is very important in ND’s
HSP70, HSP90, HSP60 (ATP dependent)
hsp small (ATP independent)
Define the HSP70 cycle
this cycle is ATP dependent and a co-chaperone
groove where misfolded protein fits –> lid closes –> ATP hydrolysed –> misfolded protein is unfolded –> lid open again –> unfolded protein had another change to fold into the correct form.
what happens if chaperones fail to refold the protein?
the misfolded protein will receive an ubiquitin tag (ubiquitin chain)
what is the function of an ubiquitin tag
This tag is added to the misfolded protein to be identifiable for degradation.
which molecule recognised the ubiquitin tag for degradation
it is recognised by the proteasome (enzyme), inside this proteasome chamber are degradative enzymes which break the amino acid backbone. The amino acids are released after degradation.
name the catalytic chamber of the proteasome
20S core particle
What is the consequence of proteasome inhibition
proteasome inhibition induces the accumulation of polyUb proteins. (ubiquitinated proteins)
define autophagy
Autophagy = The body’s way of cleaning out damaged cells, in order to regenerate newer, healthier cells
it is initiated by wrapping a membrane structure around the material that has to be degraded. it is also a manner to degrade dysfunctional mitochondria.
needed for quality control of proteins.
what are the proteolytic pathways
- proteasome = degrades monomeric proteins
2. autophagy = degrades larger structures (organelles, aggregates)
name the neurodegenerative diseases aetiology
- sporadic (majority)
- acquired (prion disease)
- genetic
define inclusion body
Inclusion bodies are dense, spherical, aggregated proteins, mostly formed in the cytoplasm of prokaryotes due to overexpression of heterologous proteins
how to mutations in aggregating proteins lead to neurodegenerative disorders
aggregates can become toxic
which neurodegenerative disease is genetic only?
Huntington’s disease
son gets 50/50 chance.
which mutation in the Huntington disease leads to toxic aggregate formation
the repeat sequence encodes for more than 35 glutamine residues to be bound together.
affects the basal ganglia and the chorea (movement)
fibril formation and ND’s are connected but not quantitively, the inclusion bodies are directly connected
ok?
explain the aggregation cascade
small oligomeric aggregates –> fibril aggregates –> fibrils deposit in inclusion bodies
which state of the aggregation cascade is the most toxic?
the oligomeric structures are the most toxic species since they are mobile and can transport to brain areas to induce damage.
are inclusion bodies toxic?
studies suggest not, since the oligomeric state provides the toxicity and inclusion bodies protect the brain from these aggregates
what is the mitotic clearance of aggregates
aggregates are removed/never present in the daughter cel.
how do aggregates disrupt neuronal function
clumps of aggregates interrupt neurotransmitter vesicle transport, directly affect synapses, localise in the synaptic cleft and interfere with neurotransmitter function or damage it directly.
What are the responses to misfolded protein stress and how are they activated
- Activated in response to accumulation of misfolded proteins
- Dependent on localization of misfolding/aggregation
- Transient response intended to restore protein folding homeostasis
- cytosol = Heat-shock response
- ER = unfolded protein response (UPR)
Explain the Heat-shock response
Heat-shock response are unregulated when there is a misfolded event.
- HSF1 sensors stress response
- Heat shock factor HSF1 Bound by Hsp Complex including Hsp70 and Hsp90
- HSP complex titrates away from HSF
- HSF trimerization and translocation to the nucleus
- activates more heat shock proteins and the proteasome
Explain the unfolded protein response (UPR
- stress sensor system (PERK, ATF6 and IRE1) –> bound by HSP70
- HSP70 binds to aggregates proteins and releases it from sensor system
- sensors activated
- induce transcription, less protein synthesis
What is Neuroinflammation
cell non-autonomous response : microglial cells and astrocytes can react to stress responses in the neuron. when activated they produce cytokines.
what is reactive astrogliosis
GFAP makes the cytoskeleton of the astrocytes. This is strongly increased in the inflammatory state, and normally reduces the stress in the neuron. Reactive astrogliosis is strongly present in ND’s
hypertrophy is also strongly unregulated in stress responses
Define the role of microglial activation in ND’s
microglia are attracted to plaques (think about the AB plaques in AD), and produce cytokines.
Microglial activation van also contribute to ND’s since the continuous high concentration of cytokines can also induce increased ROS production and reduced phagocytic response.
Define primed microglial cells
microglial cells can be in a primed state, this means they are more sensitive to stimulus.
