IIBBA   05544
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE BUENOS AIRES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Human Insulin-degrading enzyme is a target of mitochondrial biogenesis pathway and modulates mitochondrial AƒÒ accumulation.
Autor/es:
MORELLI L
Lugar:
Cancun
Reunión:
Conferencia; Nuerodegeneration Conference; 2012
Institución organizadora:
Zing Conferences
Resumen:
The proteolytic system in mitochondria is crucial for the maintenance of the organella protein turnover and integrity. Several proteases have been identified in mitochondria among which presequence protease (PreP) and Insulin-Degrading Enzyme (IDE) are the most relevant in Alzheimer`s disease (AD) in terms of their capacity to degrade amyloid b (Ab) peptide. Yet, little is known about the regulation of IDE expression and its impact on mitochondrial A£]. This limitation prompted us to characterize human IDE (hIDE) core promoter and define the molecular mechanisms involved in its transcription/translation regulation, with special interest in the long isoform starting at Met1 which translocates to mitochondria. By in silico analysis, MALDI-TOF, 5¡¦RACE, promoter deletions, luciferase assays, site directed-mutagenesis, ChiP, EMSA, mitochondria functionality tests, ELISA, Western blots, QRT-PCR, cell culture transfections and pharmacological treatments we describe that IDE-Met1 is present in human brain showing the in vivo use of the first AUG of endogenous hIDE mRNA. We define the core promoter of hIDE showing that NRF-1, a well-known regulator of mitochondrial gene expression, promotes the longest IDE mRNA (IDE-L) transcription and increases mitochondrial IDE. This correlates with a significant decrease in mitochondrial A£] (Fig. 1). Furthermore, hippocampal samples form non-demented individuals show a positive and strong correlation between the expression of master genes of mitochondrial biogenesis (PGC1-a and NRF-1) and IDE-L mRNA. By contrast, in AD brains the levels of each transcript are lower and the correlation weaker. These results suggest that the levels of IDE-L and their modulation by PGC1-a/NRF-1 may impact on mitochondrial A£] clearance and brain functionality.