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omgmbd > L19: Neurodegenerative Diseases > Flashcards

L19: Neurodegenerative Diseases Flashcards

1
Q

What are neurodegenerative disease commonly associated with?

A

→ ageing

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2
Q

What does earlier or later age of onset indicate about the genetic contribution?

A

→ greater genetic contribution

→ Later age of onset = more likely a sporadic (or idiopathic)

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3
Q

Are neurodegenerative diseases heterogenous or homogenous?

A

→ heterogeneous?

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4
Q

Define pleiotropic

A

→ producing more than one effect

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5
Q

What is the general pattern of neurodegenerative diseases?

A

→ Molecular impairment somewhere in the cell
→ Decreased transmission at synapse

→ “Dying back” of neurites (axons and/or dendrites)

→ Cell death

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6
Q

What is the distance between axon terminal and nucleus considered as?

A

→ Achilles heel

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7
Q

What are the common features of NDs?

A

→ Protein aggregation (“proteinopathies”)
→ Lysosomal dysfunction
→ Mitochondrial dysfunction
→ Associated inflammation via activation of glia

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8
Q

What is the most common cause of dementia?

A

→ Alzheimer’s

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9
Q

What is dementia?

A

→ A decline in memory and other cognitive functions that impair quality of life

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10
Q

What is the major hallmark of Alzheimers?

A

→ brain shrinkage

→ dramatic shrinkage in cortex and hippocampus

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11
Q

What are the proteinopathies of Alzheimers?

A

→ amyloid plaques

→ neurofibrillary

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12
Q

What are amyloid plaques?

A

→ Extracellular protein aggregates

→ Enriched in Aβ peptides

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13
Q

What are neurofibrillary tangles?

A

→ paired helical filaments

→ Intracellular protein aggregates

→ Enriched in Tau protein

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14
Q

What is Abeta peptide cleaved from?

A

→ transmembrane protein called amyloid beta precursor protein (APP) by proteases

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15
Q

What are the three proteins that can be mutated and involved in Abeta peptide processing?

A

→ APP
→ PSEN1
→ PSEN2

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16
Q

What are presenillin-1 and Presenillin-2 both a component of?

A

→ γ-secretase

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17
Q

What does tau normally bind to?

A

→ microtubules in axons

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18
Q

What does hyperphosphorylation of tau lead to and how?

A

→ displaced causing:
→ Tangles
→ Destabilised → microtubules

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19
Q

What are the three main roles of microtubules in post-mitotic cells?

A

→Structure/shape of cell
→ Positioning of organelles
→ Motorways for transporting vesicular cargo

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20
Q

Describe the tau hypothesis

A

→ typical late onset AD (i.e. not genetic forms of AD

→ neurofibrillary tangles are seen before amyloid plaques

→ Well correlated with cell death and progression

→ Tau is upstream Aβ

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21
Q

What are other risk factors for Alzheimers?

A 
→ Down syndrome (APP is on chromosome 21)
→ Gender (more common in women)
High BP,
 → Cardiovascular disease, Diabetes
→ Low education
→ Head injury
→ Smoking and drinking
22
Q

Which gene is most significant for contribution of late-onset AD?

A

→ APOE gene

23
Q

What is the second most common neurodegenerative disease?

A

→ Parkinson’s

24
Q

What are the motor symptoms of PD?

A

→ Resting tremor
→ Bradykinesia
→ Rigidity
→Postural instability

25
Q

What are the non-motor symptoms of PD?

A 
→ Depression & → Anxiety
→ Loss of smell
→ Sleep disorders
→ Constipation
→ Dementia
26
Q

What are the pathological hallmarks of PD?

A

→ Loss of dopaminergic neurons of the substantia nigra and other brain regions
→ Proteinopathy

27
Q

What are the staining features of PD brain of the substantia nigra?

A

→ Lack of pigmentation shows loss of substantia nigra

28
Q

What are the proteinopathies of PD?

A

→ Lewy bodies

29
Q

What are Lewy bodies?

A

→ Intracellular protein aggregates

→ Enriched in α-synuclein protein

30
Q

What is the normal role of a-synuclein?

A

→ involved in neurotransmitter release

31
Q

What does Lewy bodies do to a-synuclein protein?

A

→ increases a-synuclein

32
Q

What is the percentage of cases of PD with a clear genetic cause?

A

→ 10%

33
Q

What are the three categories familial PD?

A

→ Early/Juvenile-onset recessive mitochondrial conditions

→ Late/later-onset (usually) autosomal dominant PD

→ Mutations that cause “PD-plus” conditions- very rare

34
Q

What are some genetic causes found to be linked to PD?

A

→ SNCA (α-synuclein) gene amplification- Confirms that α-synuclein is pathogenic

→ LRRK2 gain-of-function
→ VPS35 gain-of-function
→ GBA loss-of-function- autosomal dominant, if homozygous then Gacher’s disease

35
Q

What is GBA?

A

→ GBA encodes GCase (β-glucocerebrosidase ),a lysosomal enzyme

36
Q

How is a-synuclein degraded?

A

→ degraded in the lysosome

37
Q

What happens with reduced GCase in PD?

A

→ increased a-synuclein
→ lysosome is impaired
→ autophagy reduced

38
Q

Where is GCase transported from to the lysosome?

A

→ Golgi/ER

39
Q

Explain the pathogenic feed-forward loop of GBA and a-synuclein

A

→ increased a-synuclein → reduced GCase → reduced lysosomal function

40
Q

What is consistently dysregulated in PD brains?

A

→ autophagy

→ lead to mitochondrial dysfunction

41
Q

What gene encodes tau?

A

→ MAPT

42
Q

What are other risk factors of PD?

A 
→ Gender (more common in men)
→ Red hair (~2x risk)
→ Head injury
→ Not smoking, not consuming caffeine
→ Herbicides, pesticides, insecticides
→ Exposure to metals (i.e. welder)
→ General anaesthesia
43
Q

What is neuroinflammation?

A

→ activation of the immune system within the nervous system

44
Q

Which cells are most implicated in neuroinflammation?

A

→ activated microglia

45
Q

Why are microglia implicated in neuroinflammation?

A

→ Amoeboid shape

→ More motile

→ Production of cytokines

46
Q

What are the microglial activators?

A

→ α-synuclein

47
Q

What are the neurotoxic factors?

A

→ IL-1B,
→ TNF-α,
→ prostaglandins

48
Q

How can microglia be protective?→

A

→ anti-inflammatory, e.g. TGFβ

→ normal removal of unhealthy cells (i.e. homeostasis)

49
Q

How can microglia be damaging?

A

→ pro-inflammatory, e.g. IL-1, TNF-α

→ response to pathogens etc(i.e. damage to neurons = ‘collateral damage’)

50
Q

How is the gut linked to PD?

A

→ Lewy body pathology in gut often precedes pathology in brain

→ Evidence that gut inflammation is sufficient to cause gut Lewy bodies

51
Q

What are other effects of ageing?

A

→ Shortening of telomeres in adult stem cells

→ Increased reactive oxygen species

52
Q

What are some gene expression changes as a result of ageing?

A

→ Altered Wnt signalling is a big focus in AD and PD

→ Wnts are neuroprotective and neuromodulatory

→ Wnt/β-catenin is decreased in adult brain

→ Deregulated Wnts in developmental and geriatric neuro conditions

omgmbd (29 decks)

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