General mechanisms in neurodegeneration

Question 1

what defines a neurodegenerative disorder

Answer 1

damage on different brain regions where occlusions are localised.

Question 2

What do occlusions consists out of?

Answer 2

aggregates.

Question 3

what are aggregates

Answer 3

misfolded, clustered (hydrophobic beta sheets) proteins

Question 4

what can aggregates lead to?

Answer 4

1. loss of function phenotype

2. gain of toxic function

Question 5

how are aggregates controlled

Answer 5

protein quality control

Question 6

where does protein synthesis take place

Answer 6

proteins are synthesised in the cytosol and the ER

cytosol: proteins that are packed to be transported
ER: proteins that are soluble

Question 7

what proteins prevent the binding of misfolding proteins?

Answer 7

chaperones (heat-shock proteins)

Question 8

how do HSP/chaperones prevent misfolded protein binding?

Answer 8

chaperones facilitate protein folding and refolding by keeping proteins in “a folding-competent state”

Question 9

which chaperone is very important in ND’s

Answer 9

HSP70, HSP90, HSP60 (ATP dependent)

hsp small (ATP independent)

Question 10

Define the HSP70 cycle

Answer 10

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.

Question 11

what happens if chaperones fail to refold the protein?

Answer 11

the misfolded protein will receive an ubiquitin tag (ubiquitin chain)

Question 12

what is the function of an ubiquitin tag

Answer 12

This tag is added to the misfolded protein to be identifiable for degradation.

Question 13

which molecule recognised the ubiquitin tag for degradation

Answer 13

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.

Question 14

name the catalytic chamber of the proteasome

Answer 14

20S core particle

Question 15

What is the consequence of proteasome inhibition

Answer 15

proteasome inhibition induces the accumulation of polyUb proteins. (ubiquitinated proteins)

Question 16

define autophagy

Answer 16

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.

Question 17

what are the proteolytic pathways

Answer 17

1. proteasome = degrades monomeric proteins

2. autophagy = degrades larger structures (organelles, aggregates)

Question 18

name the neurodegenerative diseases aetiology

Answer 18

1. sporadic (majority)
2. acquired (prion disease)
3. genetic

Question 19

define inclusion body

Answer 19

Inclusion bodies are dense, spherical, aggregated proteins, mostly formed in the cytoplasm of prokaryotes due to overexpression of heterologous proteins

Question 20

how to mutations in aggregating proteins lead to neurodegenerative disorders

Answer 20

aggregates can become toxic

Question 21

which neurodegenerative disease is genetic only?

Answer 21

Huntington’s disease

son gets 50/50 chance.

Question 22

which mutation in the Huntington disease leads to toxic aggregate formation

Answer 22

the repeat sequence encodes for more than 35 glutamine residues to be bound together.

affects the basal ganglia and the chorea (movement)

Question 23

fibril formation and ND’s are connected but not quantitively, the inclusion bodies are directly connected

Answer 23

ok?

Question 24

explain the aggregation cascade

Answer 24

small oligomeric aggregates –> fibril aggregates –> fibrils deposit in inclusion bodies

Question 25

which state of the aggregation cascade is the most toxic?

Answer 25

the oligomeric structures are the most toxic species since they are mobile and can transport to brain areas to induce damage.

Question 26

are inclusion bodies toxic?

Answer 26

studies suggest not, since the oligomeric state provides the toxicity and inclusion bodies protect the brain from these aggregates

Question 27

what is the mitotic clearance of aggregates

Answer 27

aggregates are removed/never present in the daughter cel.

Question 28

how do aggregates disrupt neuronal function

Answer 28

clumps of aggregates interrupt neurotransmitter vesicle transport, directly affect synapses, localise in the synaptic cleft and interfere with neurotransmitter function or damage it directly.

Question 29

What are the responses to misfolded protein stress and how are they activated

Answer 29

- Activated in response to accumulation of misfolded proteins - Dependent on localization of misfolding/aggregation - Transient response intended to restore protein folding homeostasis 1. cytosol = Heat-shock response 2. ER = unfolded protein response (UPR)

Question 30

Explain the Heat-shock response

Answer 30

Heat-shock response are unregulated when there is a misfolded event. 1. HSF1 sensors stress response 2. Heat shock factor HSF1 Bound by Hsp Complex including Hsp70 and Hsp90 3. HSP complex titrates away from HSF 4. HSF trimerization and translocation to the nucleus 5. activates more heat shock proteins and the proteasome

Question 31

Explain the unfolded protein response (UPR

Answer 31

1. stress sensor system (PERK, ATF6 and IRE1) --> bound by HSP70 2. HSP70 binds to aggregates proteins and releases it from sensor system 3. sensors activated 4. induce transcription, less protein synthesis

Question 32

What is Neuroinflammation

Answer 32

cell non-autonomous response : microglial cells and astrocytes can react to stress responses in the neuron. when activated they produce cytokines.

Question 33

what is reactive astrogliosis

Answer 33

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

Question 34

Define the role of microglial activation in ND's

Answer 34

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.

Question 35

Define primed microglial cells

Answer 35

microglial cells can be in a primed state, this means they are more sensitive to stimulus.