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Neuro Development and Disease > Neurodegenerative Diseases > Flashcards

Neurodegenerative Diseases Flashcards

1
Q

What do neurodegenerative diseases stem from?

A

the loss of specific neurons in different parts of the NS

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2
Q

Which neurons degenerate in AD?

A

neurons in the hippocampus and certain regions of the cerebral cortex

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3
Q

Which neurons degenerate in PD?

A

dopaminergic neurons in the substantia nigra pars compacta

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4
Q

Which neurons degenerate in HD?

A

neurons in the striatum

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5
Q

What neurons die in stroke patients?

A

all those supported by an occluded or ruptured blood vessel

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6
Q

What is the striatum responsible for?

A

movement

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7
Q

What is AD characterised by?

A

the loss of learning and memory capacities and psychological changes and deficits

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8
Q

What percentage of AD and PD is sporadic?

A

95%

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9
Q

What are the major pathological features of AD?

A
  • extracellular Aβ deposits in senile plaques
  • intracellular neurofibrillary triangles (NFT)
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10
Q

What are APP mutations associated with?

A
  • familial forms of early onset AD
  • Cerebral Amyloid Angiopathy (CAA)
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11
Q

What is Aβ protein?

A

the main component of senile plaques and cerebrovascular amyloid deposits

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12
Q

What do mutations in Tau cause?

A

frontotemporal dementia with Parkinsonism associated with chromosome 17 i.e. aberrant forms of tau can give rise to neurodegeneration

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13
Q

What is the main component of NFTs?

A

hyperphosphorylated Tau

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14
Q

What is the number and distribution of NFTs correlated with?

A

the degree of dementia in AD

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15
Q

What does activation of protein kinase cdk5 contribute to?

A

tau phosphorylation and neuronal apoptosis

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16
Q

What are the major causes of early onset familial AD?

A

mutations in presenilin 1 and 2 that increase the proaction of 42-Aβ which has a high propensity for forming amyloid fibrils

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17
Q

What is the most common known genetic risk factor for AD after age 60?

A

inheritance of the E4 allele

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18
Q

What does the E4 allele do?

A
  • promote the polymerisation of Aβ into plaque-forming fibrils
  • impair neuronal regeneration or promote oxidative stress
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19
Q

How is Aβ generated?

A

through a serial cleavage of APP by β- and γ-secretase

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20
Q

What does the self-aggregation of Aβ do?

A

induce membrane lipid peroxidation which can impair the function of ion pumps and glucose transporters making neurons more sensitive to apoptosis

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21
Q

What are presenilins?

A

multiple membrane spanning proteins that are important for the processing of several proteins including APP and Notch

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22
Q

What do mutant presenilins do?

A

increase the production of Aβ as well as susceptibility to apoptosis

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23
Q

What does sAPP-α do?

A

decrease Aβ generation by directly associating with BACE1

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24
Q

What does BACE1 do?

A

process APP into sAPP-β and β-CTF, which is subsequently cleaved by the γ-secretase, producing Aβ

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25
Q

What is the γ-secretase complex formed of?

A

the sequential assembly of Aph1, nicastrin, presenilin, and Pen-2

26
Q

What happens in the amyloidogenic pathway?

A

neurotoxic Aβ peptides are released after sequential cleavage of APP by β and γ-secretases, and further accumulate into oligomeric aggregates

27
Q

What is Notch secretion dependent on?

A

NICD expression by γ-secretase

28
Q

What is the amyloid cascade hypothesis?

A
  1. neurodegeneration in AD is caused by deposition of Aβ as amyloid plaques in brain tissue
  2. Aβ causes apoptosis directly in cultured neurons
  3. APP is a substrate of caspase-3 which cleaves APP to release a C-terminal apoptosis-inducing peptide
29
Q

What is present in neurons associated with amyloid deposits?

A
  • increased DNA damage
  • increased cascade activity
  • alterations in expression of apoptosis-related genes
30
Q

What is PD associated with?

A

increased oxidative stress and mitochondrial dysfunction in dopaminergic neurons

31
Q

What are pathological features of PD?

A

α -synuclein-rich Lewy bodies

32
Q

What is MPTP?

A

a precursor to the neurotoxin MPP⁺, which causes permanent symptoms of PD by destroying dopaminergic neurons

33
Q

What does inhibition of the ETC do?

A

generate ROS which damage cellular components and alter expression of redox sensitive transcription

34
Q

What is ALS?

A

a progressively fatal degenerative disease of the motor neuron leading to paralysis and death

35
Q

What are the 4 main genes that account for half of all fALS cases?

A
  • C9orf72
  • SOD1
  • FUS
  • TRADBP
36
Q

What does the C9orf72 gene contain?

A

a hexanucleotide non-coding repeat expansion responsible for many cases of ALS and frontotemporal dementia

37
Q

What is superoxide dismutase 1?

A

an antioxidant enzyme that protects the cell from ROS toxicity

38
Q

What underlies the polyglutamine expansion disorders?

A

expansion of a polyglutamine (polyQ) tract

39
Q

What is HD caused by?

A

expansion of a trinucleotide sequence (CAG) in the Huntingtin (HTT) gene

40
Q

What are symptoms of HD?

A
  • mood disorders
  • lack of coordination
  • unsteady gait
  • hyperkinetic movements
41
Q

What is HTT?

A

a large scaffolding protein with many interacting partners implicated in many processes e.g. transcription, signalling and transport

42
Q

What are mutant HTT with polyQ extensions more prone to?

A

proteolytic cleavage that generates N-terminal fragments containing the polyQ (mHTT) with a tendency to undergo misfolding and aggregation, forming fibrillar aggregates

43
Q

What do HTT aggregates do over time?

A

accumulate to form inclusion bodies within cells that interfere with neuronal function

44
Q

What are TSEs?

A

infectious diseases transmitted via an abnormal form of the prion precursor protein (PrP)

45
Q

What is prion?

A

a proteinaceous infectious particle

46
Q

Give examples of human prion diseases

A
  • CJD
  • GSS
  • fatal familial insomnia
  • kuru
47
Q

Give examples of animal prion diseases

A
  • BSE
  • TME
  • FSE
48
Q

What is the prion hypothesis?

A

normal cellular PrPC heterodimerises with PrPSC to induce transconformation

49
Q

What can defects in or large numbers of UPS lead to?

A

the pathology of several neurodegenerative diseases

50
Q

What is the known UPS dysfunction in AD, PD and HD respectively?

A
  • AD = abnormal forms of UB1
  • PD = loss of function mutation in Parkin
  • HD = aggregates blocking proteosome function
51
Q

What does balanced mitochondrial fusion and fission lead to?

A
  • redox balance
  • calcium handling
  • ↑ ATP content
  • ↑ spare respiratory capacity
52
Q

What does unbalanced mitochondrial fusion and fission lead to?

A
  • ROS overpowering
  • calcium handling defects
  • ↓ ATP content
  • spare respiratory capacity
  • mPTP opening
53
Q

What does disturbed mtDNA lead to?

A
  • increased oxidative stress
  • disturbed mitochondrial genome
  • impaired mitochondrial biogenesis
54
Q

What do AD-causing PS1 mutations do?

A

have deleterious effects on mitochondrial function

55
Q

What is a mechanism of nigral dopamine cell death in PD?

A

oxidative stress

56
Q

What does accumulation of Aβ species do?

A

activate astrocytes and microglia which migrate to the site of plaque formation and penetrate the plaques which leads to production of pro-inflammatory cytotoxic molecules such as NO and TNF-α

57
Q

What does sustained activation of microglia and other immune cells do?

A

exacerbate both amyloid and tau pathologies

58
Q

What do Aducanumab and lecanemab do?

A

lower amyloid load and marginally delay worsening of dementia

59
Q

What are the side effects of Aducanumab and lecanemab?

A

brain swelling and bleeding, or amyloid-related imaging abnormalities (ARIA)

60
Q

Give examples of neurodevelopmental disorders in children caused by neurodegeneration

A
  • Down’s syndrome
  • lysosomal storage diseases
  • various peroxisomal and mitochondrial disorders
  • ciliopathies
  • autism spectrum disorder
61
Q

What is Rett syndrome?

A

a neurodevelopmental autism spectrum disorder of young females that arises due to epigenetic alterations

62
Q

What is Rett syndrome characterised by?

A

profound cognitive impairment, communication dysfunction and postnatal growth defects

Neuro Development and Disease (9 decks)

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