Neuro - Tauopathies and FTD

Question 1

Where is Tau normally P at?

Answer 1

A range of serine and threonine residues

Question 2

Does phosphorylation of Tau positively or negatively regulate binding of Tau to MTs?

Answer 2

Negatively

Question 3

What is the biological role of Tau?

Answer 3

It is a MT associated protein largely localized to the neuronal axons. Important biological role in stabilizing MTs through promoting MT polymerization. Therefore aids neuronal structure and axonal transport.

Forms rigidity to the MT.

Question 4

Does P-Tau bind to MT?

Answer 4

No

Question 5

What does hyper-P Tau form?

Answer 5

Paired helical filaments

Question 6

What are paired helical filaments of Tau the building blocks of?

Answer 6

Building blocks of neurofibrillary tangles.

Two twisting strands with an apparent periodicity of 80nm and an alternating width between 8 and 20nm.

Aggregate into insoluble filamentous amyloid deposits in neuronal cell bodies/processes and glia - neurofibrillary tangles.

This process either leads to neuronal dysfunction and death or is a marker of neuronal death.

Question 7

What are the genetic factors which can lead to Tau dysfunction?

Answer 7

Tau mutations, APP/PS1/PS2 mutations or other mutations

Question 8

What do the genetic factors in Tau dysregulation cause?

Answer 8

Perturbation of 4R/3R ratio, loss of Tau function and gain of toxic function which leads to tau dysfunction, aggregation and MT loss resulting in impaired transport and neurodegeneration

Question 9

What are pick inclusion bodies?

Answer 9

Tau-positive spherical, cytoplasmic neuronal inclusions, composed of straight filaments

Question 10

Where are NFTs and neuritic threads found in the brain?

Answer 10

Gray matter of the frontal cortex

Question 11

Where are perinuclear inclusions found in the brain?

Answer 11

Frontal cortex

Question 12

What are the 3 types of tau immunopositive inclusions

Answer 12

Pick inclusion bodies
NFTs and neuritic threads
Perinuclear inclusions

Question 13

Name the 7 diseases involved with Tau positive inclusions in neurodegenerative diseases

Answer 13

Alzheimer’s disease, Corticobasal degeneration, GUAM, Pick’s disease, FTDP17, Dementia pugilistica and progressive supranuclear palsy.

Question 14

Can tau be a secondary pathological event in other neurodegenartive disorders?

Answer 14

Yes - alpha-synuclein aggregates with tau in neurones carrying the A53T mutation in PD.

Huntingtin inclusions colocalise with tau in neurons from Huntington’s disease patients

Question 15

What part of the amyloid cascade causes the alter metabolism of tau?

Answer 15

Neuronal injury by A-beta peptide accumulation

Question 16

How can you image Tau in the brain?

Answer 16

PET scanning with PBB3 which binds to Tau and detects NFTs

Possibility for biomarkers

Question 17

What are the 3 main areas which tau mutations can effect?

Answer 17

Mutations impairing Tau protein function
Mutations promoting Tau aggregation
Mutations altering exon 10 splicing

Question 18

Which form of tau is more likely to aggregate?

Answer 18

Ones with 4 repeats of tubulin binding domains

Question 19

What are the clinical features of FTD?

Answer 19

55-65 onset
Male>Female
Prominent frontal lobe symptoms:
- Personality changes
- Loss of socially accepted behavior
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