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Digital archive of theses discussed at the University of Pisa

 

Thesis etd-09042019-151341


Thesis type
Tesi di laurea magistrale
Author
MADARO, GIUSEPPE
URN
etd-09042019-151341
Thesis title
Disentangle the link between nuclear Tau and gene expression regulation
Department
BIOLOGIA
Course of study
BIOTECNOLOGIE MOLECOLARI
Supervisors
relatore Dott.ssa Di Primio, Cristina
tutor Prof.ssa Raffa, Vittoria
Keywords
  • Epigenetics
  • Gene expression regulation
  • Neurodegeneration
  • Nuclear Tau
  • Tauopathies
Graduation session start date
23/09/2019
Availability
Full
Summary
The formation of insoluble aggregates of the protein Tau is a common feature of a group of neurodegenerative diseases known as tauopathies. Recent studies have proposed a plethora of non-canonical functions for this tubulin binding protein, which may explain the distinctive pathological features. Our group has recently discovered that nuclear Tau is involved in gene expression regulation of disease-related genes such as VGluT1 and NMDA receptors, ultimately impinging on synaptic transmission.
I investigated the molecular mechanism by which Tau modulates VGluT1 expression. Since the transcriptional co-repressor TRIM28 has been reported to mediate nuclear Tau accumulation, I studied the molecular interaction between Tau and TRIM28 exploiting the Y2H technique. Then, I performed Tau protein dissection to test which of its domains retains the ability to increase VGluT1 expression in human cell lines. To analyse the interaction between Tau and TRIM28 cofactors involved in gene repression, such as HDAC1, I performed overexpression and KD experiments. Moreover, I measured the global HDACs activity in the nuclear compartment of cells overexpressing Tau. To further investigate the involvement of nuclear Tau in TRIM28 complex rearrangements, I observed the relocation of its cofactors in the nuclear compartment through imaging experiments.
Preliminary results indicate that TRIM28-HDAC1 complex is hampered by Tau over-expression. Nevertheless, HDAC1 knock-down alone is not enough to enhance VGluT1 expression. In conclusion, Tau might modulate gene expression by altering the chromatin structure through a mechanism that will be deeply investigated.
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