| Title: | Dissecting the role of REEP1 in preventing Tau-mediated neurodegeneration in a D.melanogaster Alzheimer's disease model |
|---|
| Authors: | ID Feiguin, Fabian (Mentor) More about this mentor... 
ID Guglielmi, Alessio (Author) |
|---|
| Files: |  Alessio_Guglielmi.pdf (2,59 MB)
MD5: A73EAF6C652B5BDF46E327A284B2A593
|
|---|
| Language: | English |
|---|
| Work type: | Doctoral dissertation |
|---|
| Typology: | 2.08 - Doctoral Dissertation |
|---|
| Organization: | FPŠ - Graduate School
|
|---|
| Abstract: | Tau is natively an unfolded protein that promotes the assembly and the stability of the
axonal microtubules in the central nervous system. Increased formation of Tau protein
aggregates has been causatively implicated in several neurodegenerative diseases called
tauopathies. In the present study, we used the Drosophila melanogaster system to express
the longest isoform of human Tau (2N4R) in the nervous system of adult flies, recreating
the main features of the human pathology. Herein, this Tau-mediated neurodegeneration
model was used as a platform to perform genetic screenings to identify putative modifiers
of Tau toxicity. Our strategy exploited the modulation of genes considered as risk factors of
Alzheimer’s disease (AD), Frontotemporal Dementias and other neurodegenerative
diseases by RNA interference in vivo. This approach allowed us to identify a new gene
which participates in the neuronal response against Tau induced neurotoxicity in
Drosophila: D-Reep1, homologue of human REEP1 gene (h-Reep1). D-Reep1 knockout flies
showed no apparent phenotypes in physiological growing and developmental conditions,
however, they showed peculiar sensitivity to stress conditions. In addition, D-Reep1
knockout enhanced the neurodegeneration mediated by Tau expression in Drosophila eyes.
On the contrary, the overexpression of UAS-D-Reep1 and UAS-h-Reep1 abolished the
typical rough eye phenotype induced by the presence of Tau. The Co-expression of D-Reep1
in Tau backgrounds did not alter the phosphorylation pattern of this protein while, the
presence of D-Reep1 seemed to prevent the formation of Tau aggregates in vivo. Thus, the
data support the idea that D-Reep1 exerts a protective role on Tau induced toxicity which is
independent of its phosphorylation status. In this work, I analysed the mechanisms behind
the neuroprotective role of D-Reep1 and, in particular, I found that REEP1 is involved in the
regulation of the unfolded protein response (UPR) through the PERK-ATF4 cascade within
the ER. By the activation of this pathway, the neurotoxic aggregates of Tau are removed
from Drosophila neuronal tissues rescuing the normal characteristics of the affected
tissues. Evidences also suggest that the activation of autophagy was behind the removal of
Tau aggregates, providing new molecular information about the physiological role of D
Reep1 in the nervous system. |
|---|
| Keywords: | AD Alzheimer Disease APP Amyloid precursor protein CNS Central Nervous System DM Drosophila melanogaster HSP Hereditary Spastic Paraplegia LN Lewy’s neurite MT Microtubule MAP Microtubule associated protein MT Microtubule/s MTBD Microtubule binding domain NFT Neurofibrillary tangle NP Neuritic plaques PHF Paired helical filament PS1 Presenilin 1 PS2 Presenilin 2 SPG Spastic Paraplegia ThS Thioflavin S |
|---|
| Place of publishing: | Nova Gorica |
|---|
| Year of publishing: | 2019 |
|---|
| PID: | 20.500.12556/RUNG-4778-bbfefcf0-a926-e473-9d6b-9286c5766144 |
|---|
| COBISS.SI-ID: | 5498619 |
|---|
| NUK URN: | URN:SI:UNG:REP:XR9BPBFH |
|---|
| Publication date in RUNG: | 06.12.2019 |
|---|
| Views: | 3369 |
|---|
| Downloads: | 119 |
|---|
| Metadata: |     |
|---|
|
:
|
Copy citation |
|---|
| | | | Average score: | (0 votes) |
|---|
| Your score: | Voting is allowed only for logged in users. |
|---|
| Share: |  |
|---|
Hover the mouse pointer over a document title to show the abstract or click
on the title to get all document metadata. |
