Lecture 11- AD part 2

Question 1

What is Tau and what is its role?

What do we need to know about the microtubule system?

What is the molecular link between amyloid deposition and tau aggregation?

What does autophagic protein degradation got to do with it and to what extend can mTOR regulation affect aggregation?

Question 2

Tau

Answer 2

Tau is a neuronal cytosolic protein
Predominantly expressed in axons (hardly in glial cells)
Stabilizes microtubules
Tau is highly soluble, natively unfolded protein with little secondary structure
C-terminal half: contains 3-4 imperfectly repeated motifs involved in binding to microtubules
N-terminal half: projects away from the microtubule surface
Abnormal aggregates of Tau (neurofibrillary tangles consisting of paired helical filaments PHFs) are hallmarks of AD and tauopathies
Aggregation of tau is based on the repeat domain and its tendency to convert to beta-structure
Elevated levels of fragmented tau in the CSF is an early marker for AD
Tau can be degraded by lysosomal cathepsins (cathepsin D)
It is unclear whether tau is normally degraded by the autophagic system or proteasome system (ubiquitination) or both
Tau hyperphosphorylated at Ser-Pro or Thr-Pro flanking the repeat domain can be ubiquitinated
Inhibition of lysosomes can increase tau levels

Question 3

Question 4

Tau can be cleared by macroautophagy
Inhibition of macroautophagy leads to enhanced aggregation and cytotoxicity of the mutant tau
Macroautophagy can also degrade the full length tau
Phosphorylation in the repeat domain, which regulates its tubulin affinity, does not alter its sensitivity to autophagy-lysosomal degradation
association of tau to lysosomes via LAMP-2A seems to may interfere with normal lysosomal function
Changes in lysosomal degradation of Tau as well as direct effects of Tau on lysosomes can contribute to pathogenesis in AD

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