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ATU 1 > Neuro - general > Flashcards

Neuro - general Flashcards

1
Q

Symptoms of PD?

A 
Akinetic-rigid
Bradykinesia
Loss of movement
Increased muscle tone
Resting tremor
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2
Q

Is PD predominantly inherited or non-inherited?

A

Non-inherited

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3
Q

Where are dopamine neurons lost on PD?

A

SN - 50% lost for symptoms and 80% at autopsy

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4
Q

Where are cells lost in PD?

A 
Substantia nigra
Locus ceruleus
Dorsal motor of the vagus
Raphe nuclei
Brain stem structures
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5
Q

Describe lewy bodies

A 
Spherical
Intracellular
Eosinophillic core
Pale halo
Filamentous and granular material
Neurofilament proteins, Ubiquitin and Lipids
Major alpha-syn
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6
Q

What are the PARK genes?

A

15 causing genes

PARK 1/4, 2, 5 and 8 all found to be involved in membrane trafficking and UPS

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7
Q

Describe alpha-syn

A

PARK1/4
140aa protein
found at presynaptic terminals
Thought to be involved in synaptic plasticity, membrane trafficking and vesicle sorting
Mutations can cause aggregation (A53T, A30P, E46T and WTx3 Iowan)
Gene replication can cause PD
Aggregable (also found in AD plaques)
Upon binding to membrane it forms an amp alpha helix
Central hydrophobic region self-associates and aggregates (region not shared with beta-syn)
C-terminal acidic tail inhibits aggregation hence why truncation can lead to aggregation
A53T - 50% longer half-life than the WT shows it is not degraded as efficiently
Contains a KFERQ-like motif - think CMA dominant degradation pathway with LAMP2A/Hsc70 but cannot be translocated into the lumen which enhances aggregation and blocks other protein degradation
PD neurons have decreased levels of Cathepsin D, LAMP-2A and Hsc70
Macroautophagy which can degrade aggregates is also inhibited - rapamycin which inhibits mTOR stimulates macroautophagy which promotes alpha-syn aggregation clearance

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8
Q

Describe LRRK2

A

PARK 8
Leucine-rich repeat kinase
Mutated forms found in PD - G2019S
Member of the ROCO family contains a MAPKKK (kinase effector domain) and a ROC-GTP domain (GTP binding regulation domain)
G2019S found in the MAPKKK domain
In rats vectors containing LRRK2 were injected in one side of the brain - KO of LRRK2 cause neurite outgrowth and branching whereas G2019S caused no neurite outgrowth or branching. Suggests that the mutations cause P of its targets without regulation one of its targets is Tau
Found in the striatum
See a reduction of LRRK2 in PD dopamine neurones

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9
Q

Describe Parkin

A

PARK 2
Encodes a E3 Ub-ligase and is thought to be protective against PD
Can bind Ub and alpha-syn and target it for degradation
Mutations cause loss of function and therefore PD by getting alpha-syn build up
Overexpressed Parkin and alpha-syn and looked at dopamine neurones by staining for tyrosine hydroxylase

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10
Q

Describe UCHL1

A

PARK 5
De-Ub enzyme - removes Ub from the C-terminal bond
Mutations are loss of function and cause PD/PD-like syndromes
Present in Lewy bodies
Important for keeping the Ub pool in the cell - can inhibit other protein degradation by not restoring the Ub pool

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11
Q

Describe PINK1

A

Serine/threonine protein kinase
N-terminal mitochondrial localization signal
Protects the cell against apoptosis induced by proteasome inhibition
Loss of function causes PD

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12
Q

Describe DJ-1

A

Redox sensitive molecular chaperone
Loss of function leads to PD through sensitivity to oxidative stress
L166P mutation promotes cytoplasm –> mitochondria

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13
Q

Treatments for PD - autologous graft

A

Take adrenal chromaffin cells from the same patient and transplant into the striatum and they release dopamine
No immunosuppresion needed
Stopped as saw adverse psychiatric effects

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14
Q

Treatments for PD - fetal transplant

A

Take SN from aborted fetuses and transplant into the caudate nucleus
Worked well but side effects of Bradykinesias
Ethical issues - need 6-8 fetuses as 90% of cells die, needed immunosuppression

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15
Q

Treatments for PD - stem cells

A

Take stem cells either from a different organism or the same one and induce to differentiate into DA neurons
Transplants in aminal models but number of problems - hard to get the stem to stop dividing so DA tumor

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16
Q

Treatments for PD - Deep brain stimulation

A 
Place electrodes into the STN
Pacemaker fitted so patient can control
Mimic a lesion to reverse the signals
Works quickly
Tends to be done in younger patients as better for op
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17
Q

Treatments for PD - Growth factors and gene therapy

A

Gene therapy:
Lentivirus and adenovirus vectors contain a gene e.g. parkin or tyrosine hydroxylate
Delivery to specific area can be problematic and crossing BBB - conbine with transplant - Varying sucess in animals

Growth factors:
Infuse with a catheter as cannot cross BBB
Close to the striatum
GDNF - dissapointing
Neurturin
GDF5 - preclincal development
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18
Q

When was AD first discovered?

A

1907 by Alois Alzheimer

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19
Q

What is the most common form of dementia

A

AD of 80% of cases

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20
Q

Symptoms of AD?

A

Changes in personality, memory loss, confusion, hallucinations and many more

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21
Q

Who donated her brain to AD research and what did he find?

A

Auguste Deter

Found plaques and tangles

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22
Q

What is the first region affected in AD? then where?

A

Hippocampus then spreads to the frontal lobes/back of the brain then throughout the cortex regions

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23
Q

What is the average number of years after diagnosis for AD?

A

8 years but varies

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24
Q

Draw the amyloid cascade theory

A

See diagram

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25
Q

Draw A-beta production

A

See diagram

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26
Q

What are the proteins which make up gamma secretase?

A

PS1/2, Pen2, Aph1a/b and Nicostatin

27
Q

How many different isoforms of gamma secretase?

A

4 vary in PS1/2 and aph1a/b

28
Q

What is the ratio of sporadic AD to familial

A

90% and 10%
Early onset/familial before 65 years
Pathologies are similar​ so can inform us

29
Q

What are the genes which cause early onset/familial AD?

A

Mutations it APP, PS1 and PS2

30
Q

What does the Swedish mutation cause in APP?

A

Increases beta-secretase cleavage

31
Q

What does the Flemish mutation cause in APP?

A

Changes the A-beta structure which causes it to aggregate quicker

32
Q

What do the Florida and Australian mutations cause in APP?

A

more 42 production which is less soluble and aggregates quicker therefore more toxic

33
Q

Mutations in PS1/2 cause?

A

More 42 production - cause APP to move more inside the cleavage site causes change in 42 vs 40 ratio

34
Q

Down syndrome and AD?

A

Trisomy 21
Where APP is located so more A-beta over their life-time
Early onset at late 30s

35
Q

Protection mutation in AD?

A

A673T
People over 85+ without AD
20% less A-beta production
Protects against cognitive decline

36
Q

Neurotoxic form of a-beta?

A

Soluble oligomers/pores
Can move around the body and bind to membranes in the synapses altering comminucations –> toxic and death
Oligomers induce oxidative damage and hyper-P of tau which forms NFTs

37
Q

What are the pathways which degrade A-beta?

A

IDE, RAGE, A2M and LRP

38
Q

Risk factors in sproadiac AD?

A 
ApoE
PICALM
CLU
CR1
Found during a huge meta-analysis project in 2013
39
Q

ApoE?

A

Apolipoprotein of the HDL complex in the brain
Can bind A-beta
Different isoforms of ApoE generally thought to reduce A-beta however the E4 isoform increases Ab depoistition whereas E2/3 decrease it

40
Q

What are the symptomatic relief for AD?

A

Neurotransmission is distrupted so NMDA anatagonist and chloinesterase inhibitors

41
Q

What are the three areas for potential therapies in AD?

A

1) A-beta production - alpha increase, beta and gamma decrease and alter APP trafficking
2) . A-beta degrdation - activation of degradation enzymes e.g. ICE, ACE, ECE-1 and immuno therapy
3) . A-beta aggregate formation - prevent toxic effects and allow easier degrdation

42
Q

What is the function of Tau?

A

MT associated protein
Binds and stabilizes MTs by promoting polymerisation aiding neuronal axonal transport and structure
When P at are range of serine/threonine residues prevents binding to MT therefore inhibits transport down the axon

43
Q

What does hyper-P of Tau do?

A

Impairs normal function and also forms paired-helical filaments which are the building blocks of neurofibril tangles which are insoluble amyloidogenic aggregates in neuronal cell bodies/processes and glia leading to neuronal dysfunction/death or a marker of neuronal death

44
Q

What are the genetic factors associated with Tau dysfunction?

A

Tau mutations, APP/PS1/2 mutations or other
Perturbation of 4R/3R ratio, loss of Tau function and gain of toxic function which leads to Tau dysfunction, aggregation and MT loss then impaired transport and neurodegeneration

45
Q

What are the 3 types of Tau immunopositive inclusions?

A

Pick inclusion bodies which are tau-positive, spherical, cytoplasmic inclusions composed of straight filaments

NFTs/neuritic threads in the gray matter of the frontal cortex

Perinuclear inclusions of the frontal cortex

46
Q

Names 3 tau-positive inclusion diseases

A

AD
FTDP17
Pik’s disease
Dementia pugilistica

47
Q

Which diseases is tau a secondary event in?

A

AD
PD - alpha-syn colocalizes with tau in neurons carrying the A53T mutation
Huntington’s - inclusion colocalize with tau in neurons

48
Q

How can we image Tau and A-beta?

A

PET scans with PiB for A-beta amyloid and PBB3 for Tau

Possibilty for biomarkers

49
Q

Known tau mutations leading to neurodegeneration

A

Mutations impairing tau protein function - G272V
Mutations promoting tau aggregation - G272V
Mutations altering exon 10 splicing - D280K

50
Q

Is there different isoforms of Tau?

A

Yes - caused by different splice variants
4 repeat forms of Tau lead to increases aggregation
Have different biological roles within the brain
Can have different post-translational modifications such as P

51
Q

Clinical features of FTD

A

Clinical group of neurodegenerative syndromes
Mean age 55-65
Male>Female
Frontal lobe symptoms e.g. personality changes, loss of socially acceptable behaviour, language dysfunction, movement disorder
Internation research criteria for diagnosing

52
Q

What percentage of dementia is FTD?

A

10-15% in the US

More common than AD below 60

53
Q

What are the 3 neuro-circuit effects in AD?

A

Dorsolaterol prefrontal cortex
Anterior cingulate cortex
Orbitofrontal cortex
Give different symptoms - very hard or doctors to recongise whats happening

54
Q

Draw the subtypes of FTD

A

See diagram

55
Q

FTD inheritance? Which chromosomes are effected?

A

Autosomal dominant pattern of inheritance - 10% have a single gene mutation
Chromosomes 3p, 9, 9p and 17q

56
Q

What are the most prevelant genes in FTD? and which others?

A

Progranulin and tau located on 17q21
TDP43
FUS
C9ORF72

57
Q

The autosomal dominant form of FTD?

A

FTDP-17 linked to chromosome 17q21

58
Q

What are the 2 main hallmarks of clinical FTD?

A

FTLD

1) . histopathologic diagonosed with neuronal and gliosis, spongiosis and ballooned neurons
2) . Abnormal protein inclusions: tauopathies (Tau+), TDP-43 (Tau= but TDP43 and Ub+) or FUS (Tau neg but FUS and Ub+)

59
Q

What are the functions of TDP-43?

A 
TAR DNA binding protein
Transcription regulation
Exon splicing
mRNA stablisation
Neuronal activity-response factor
60
Q

Is TDP-43 inclusions amyloidogenic?

A

No

61
Q

What are the potential mechanisms of TDP-43 neurodegeneration

A

Aggregation and sequestration of TDP-43 leading to either dystrophic neurites, cytoplasmic inclusions or intranuclear inclusions
All loss of function or can have toxic gain of function

62
Q

Current drugs for FTD?

A

Antipsychotics (block dopamine), antidepressants and NMDA receptor antagonists

63
Q

Targets in FTD for drugs?

A

Tau kinases inhibit the P
Inhibit the tau filrillizstion
MT stablising agents
TDP-43 inhibitting aggregation

ATU 1 (11 decks)

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