L19: Neurodegenerative Diseases Flashcards by BLACK H

What are neurodegenerative disease commonly associated with?

→ ageing

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

→ greater genetic contribution

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

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Are neurodegenerative diseases heterogenous or homogenous?

→ heterogeneous?

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Define pleiotropic

→ producing more than one effect

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What is the general pattern of neurodegenerative diseases?

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

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

→ Cell death

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

→ Achilles heel

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What are the common features of NDs?

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

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What is the most common cause of dementia?

→ Alzheimer’s

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What is dementia?

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

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What is the major hallmark of Alzheimers?

→ brain shrinkage

→ dramatic shrinkage in cortex and hippocampus

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What are the proteinopathies of Alzheimers?

→ amyloid plaques

→ neurofibrillary

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What are amyloid plaques?

→ Extracellular protein aggregates

→ Enriched in Aβ peptides

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What are neurofibrillary tangles?

→ paired helical filaments

→ Intracellular protein aggregates

→ Enriched in Tau protein

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What is Abeta peptide cleaved from?

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

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

→ APP
→ PSEN1
→ PSEN2

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

→ γ-secretase

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What does tau normally bind to?

→ microtubules in axons

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What does hyperphosphorylation of tau lead to and how?

→ displaced causing:
→ Tangles
→ Destabilised → microtubules

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

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

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Describe the tau hypothesis

→ 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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What are other risk factors for Alzheimers?

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

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

→ APOE gene

What is the second most common neurodegenerative disease?

→ Parkinson’s

What are the motor symptoms of PD?

→ Resting tremor
→ Bradykinesia
→ Rigidity
→Postural instability

What are the non-motor symptoms of PD?

``` → Depression & → Anxiety → Loss of smell → Sleep disorders → Constipation → Dementia ```

What are the pathological hallmarks of PD?

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

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

→ Lack of pigmentation shows loss of substantia nigra

What are the proteinopathies of PD?

→ Lewy bodies

What are Lewy bodies?

→ Intracellular protein aggregates → Enriched in α-synuclein protein

What is the normal role of a-synuclein?

→ involved in neurotransmitter release

What does Lewy bodies do to a-synuclein protein?

→ increases a-synuclein

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

→ 10%

What are the three categories familial PD?

→ Early/Juvenile-onset recessive mitochondrial conditions → Late/later-onset (usually) autosomal dominant PD → Mutations that cause “PD-plus” conditions- very rare

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

→ 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

What is GBA?

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

How is a-synuclein degraded?

→ degraded in the lysosome

What happens with reduced GCase in PD?

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

Where is GCase transported from to the lysosome?

→ Golgi/ER

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

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

What is consistently dysregulated in PD brains?

→ autophagy | → lead to mitochondrial dysfunction

What gene encodes tau?

→ MAPT

What are other risk factors of PD?

``` → 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 ```

What is neuroinflammation?

→ activation of the immune system within the nervous system

Which cells are most implicated in neuroinflammation?

→ activated microglia

Why are microglia implicated in neuroinflammation?

→ Amoeboid shape → More motile → Production of cytokines

What are the microglial activators?

→ α-synuclein

What are the neurotoxic factors?

→ IL-1B, → TNF-α, → prostaglandins

How can microglia be protective?→

→ anti-inflammatory, e.g. TGFβ | → normal removal of unhealthy cells (i.e. homeostasis)

How can microglia be damaging?

→ pro-inflammatory, e.g. IL-1, TNF-α → response to pathogens etc(i.e. damage to neurons = ‘collateral damage’)

How is the gut linked to PD?

→ Lewy body pathology in gut often precedes pathology in brain → Evidence that gut inflammation is sufficient to cause gut Lewy bodies

What are other effects of ageing?

→ Shortening of telomeres in adult stem cells | → Increased reactive oxygen species

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

→ 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