Tuesday, 21 November 2017
NUTRIENT-MEDIATED SIGNALING UNIT  

 

  Web:http://www3.ibv.csic.es/ibv03/USN/usn-index.php

 

The main goal of our laboratory is to understand how glucose i sable to regulate the cellular energetic metabolism y how the dysregulation of this process is able to produce human diseases. The Unit has currently two complementary research lines:

1.- Study of the glucose signaling pathway and its pathophysiological implications.

One of the main components of the glucose signaling pathway in mammals is the AMP-activated protein kinase (AMPK). This protein is the main energy sensor in cellular physiology. It is activated by energy stress conditions, leading to the activation of catabolic pathways which provide ATP to the cell, and also to the inactivation of anabolic pathways which consume this nucleotide, with the aim to maintain cellular energy homeostasis. AMPK plays a key role in a great variety of cellular processes. Among them, we are particularly interested in the role of AMPK at the central nervous system (CNS), where it plays a neuroprotective role, alleviating a great variety of neurodegenerative diseases. Our group is interested in the development of new AMPK activators that could modulate the function of this enzyme in the CNS.

2.- Study of the molecular basis of progressive myoclonus epilepsy of Lafora type (LD, OMIM 274780).

 

LD is a rare neurodegenerative disease characterized by generalized seizures and polyglucosan accumulations in brain and different peripheral tissues. It is an autosomal recessive disease leading to the death of patients about ten years after the debut of the first symptoms. Our group has described that laforin (a dual phosphatase) and malin (an E3-ubiquitin ligase), two LD-related proteins, form a functional complex suggesting that both proteins operate in a common physiological process. One of the functions of this complex is to decrease R5/PTG levels, a protein involved in the regulation of glycogen synthesis. In this complex, laforin acts as a targeting subunit, recruiting specific substrates to be modified by the E3-ubiquitin ligase activity of malin and then targeted for degradation in the proteasome or the autophagy pathway. We are currently studying the function of the laforin-malin complex in the regulation of glycogen homeostasis, to define the molecular bases that are altered in LD disease which lead to the accumulation of polyglucosan in neurons and other tissues. Our group has also shown that in the absence of laforin or malin macroautophagy is inhibited, probably at the level of the initial stages. We are currently studying the molecular basis of this deficiency. Finally, Lafora disease is characterized by the appearance of generalized seizures. Recently we have demonstrated a dysfunction in the homeostasis of the glutamate transporter EAAT2 in astrocytes from LD models, and also the presence of neuroinflammation in animal models of the disease. We are currently studying whether these alterations could explain the appearance of epilepsy in LD. We hope that the studies we are conducting on the pathophysiological basis of the disease will allow us to identify processes that are altered in LD, so we could propose therapeutic approaches in order to get an effective treatment for this fatal disorder.

 

 

 

 

 Principal Investigator:

 Pascual Sanz

 
 
Currículum Vitae

Publications

Teléfono: 963391760

Email: sanzibv.csic.es 

 
     
 
  • Sanz Bigorra, Pascual
  • Viana Ballester , Rosa
  • García Gimeno, Maria Adelaida
  • Heredia Pérez , Miguel
  • Molla Moliner, Belen
  • Perez Jimenez, Eva
  • Sanchis Gandia, Ana