L9, Signalopathies I

Question 1

Key neurodegenerative diseases caused by calcium signalling dysregulation:

Answer 1

• AD
• PD
• HD
• Prion disease

Question 2

Types of AD:

Answer 2

• Late-onset: After 65yrs, most common
• Early-onset: 30-65, rare, often progresses more rapidly than late-onset AD

Question 4

Hallmarks of AD:

Answer 4

Formation of neurofibrillary tangles:

• Phosphorylation of tau protein by GSK-3
• Aggregation of phosphorylated tau proteins into tangles
• Removal of tau protein interferes with neuronal transport (destabilising microtubules)

Amyloid plaques: (outside neurons)

• Cleavage of amyloid precursor protein (APP) -> beta amyloid fibres
• Polymerisation of AB fibres -> beta amyloid plaques
• Abnormal amyloid levels bring about neuronal cell death

Question 5

Classifications of AD:

Answer 5

• Familial AD (follows a certain inheritance pattern)
• Sporadic AD: Amyloidogenic pathway + Ca2+ signalosome remodelling with age -> severe cognitive decline + neuronal cell death

Question 6

Amyloid cascade hypothesis (Non-amyloidogenic pathways):

Answer 6

• Beta amyloid precursor protein synthesised in the ER-golgi, transferred to the PM
• APP cleaved by alpha-secretases -> soluble APPa and the C terminal fragment a in the membrane
• CTFa hydrolysed by PS1 releasing APP intracellular domain (a TF)
• APP is recycled through endosomal pathway -> No AB release

Question 7

Amyloid cascade hypothesis (Amyloidogenic pathways):

Answer 7

• Internalised APP is cleaved by B-secretases (part of BACE) to produce the C-terminal fragment B
• CTF is hydrolysed by gamma-secretase releasing AB (and AICD)
• Aggregation of AB monomers to form AB oligomers, fibrils and plaques
• Interaction of AB oligomers with the cellular prion protein (PrPc) -> apoptosis
• N-terminal sAPPB is hydrolysed to N-terminal APP (N-APP)
• N-APP (through the DR6 receptor) activates caspases-3 (leading to apoptosis) ad caspase-6 (leading to axon pruning)

Question 8

How do AB oligomers cause calcium influx?

Answer 8

• Cellular prion protein interaction allows receptor action -> Ca2+ influx
• AB oligomer insert into membrane to form channels -> Ca2+ influx
• Enhance Ca2+ entry through ROCs: NMDA receptor (NMDAR)

Question 10

Presenilins: Role in calcium release

Answer 10

• PS ‘leak Calcium from the ER (pressure valve), maintaining ER calcium at a low level (hippocampal dendrite spine cytosol via SOCs)

Question 11

Mutations in PS1 that cause early onset FAD:

Answer 11

• Increased Calcium release from ER
• Reduce Calcium influx into hippocampal spines via SOCs
• Enhance IP3R/RYR-mediated Calcium release due to beta-amyloid

Question 12

Role of ROS in calcium release:

Answer 12

• Act as IP3R agonist

Question 13

Consequence of Calcium dysregulation in AD:

Answer 13

• Calcium-induced apoptosis
• Calcium/ROS-associated astrocyte-induced neuronal cell death (astrocytes support neurons in the CNS)
• Disruption of synaptic plasticity, learning and memory

Question 14

How is calcium involved in apoptosis?

Answer 14

• Increase in cytosolic calcium
• Release of mitochondrial cytochrome c
• Apoptosome formation; caspase activation, cleavage of proteins and DNA

Question 15

How does disruption of calcium homeostasis disrupt synaptic plasticity?

Answer 15

• Synapses undergo modifications of synaptic efficiency
• Calcium induced changes in the sensitivity of the AMPA receptor (AMPAR) to glutamate in dendritic spines (LTP and LTD)
• High calcium: Phosphorylation by activated CaMKII and enhanced sensitivity to glutamate -> LTP and memory formation
• Low calcium increases: Dephosph. by activated CaN, reduced sensitivity to glutamate -> LTD and erasure of temporary memory (overactive in AD patients since basal calcium is constantly elevated)