APACHE: THE NEW PROTEIN THAT GUIDES THE DEVELOPMENT OF THE NERVOUS SYSTEM

We have some clues, but still few ideas about how the protein works and about its real complexity: this is what makes the project particularly intriguing and fun”. Fabrizia, red hair and blue eyes, cannot hide her enthusiasm: a former student of Biotechnology at our University, Dr. Guarnieri is now a PostDoc in the  Neuropsychopharmachology Unit at San Raffaele Hospital, and is among the authors of the study published on Cell Reports describing the discovery of  a new protein – APache – involved in the development and proper functioning of the nervous system.

The results open the door to further research that could contribute to the understanding of many neurodegenerative diseases, such as Alzheimer’s disease, and to the development of targeted therapeutic strategies.

A HINT FROM THE UNITED STATES

Prof. Flavia Valtorta, Head of the Neuropsychopharmacology Unit and Full Professor of Pharmacology at our University, says: “The idea of this research comes from the collaboration with an American group. Jonathan Wren, bioinformatician and researcher in Oklahoma City, had contacted us several years ago with a proposal: he had developed a method to predict the possible function of uncharacterized genes based on the analysis of a vast amount of genetic data – big data – with a pure infomatics approach. He came to us with a list of uncharacterized genes, some of which could have interested us as, according to his predictions, they were possibly involved in the processes we were studying in our laboratory, such as the transmission of information in the central nervous system and the release of neurotransmitters”. Among the proposed genes, the research group has finally focused on one, “which was virtually unknown in the literature and that therefore could be the most interesting to study”.

The Neuropsychopharmacology Unit. Prof. Valtorta is second row, third from left; Dr. Guarnieri is first row, first from left.
The Neuropsychopharmacology Unit. Prof. Valtorta is second row, third from left; Dr. Guarnieri is first row, first from left.

This project – recalls Prof. Valtorta – was born with Dr. Eugenio Fornasiero, today a researcher in Gottingen, then was ‘inherited’ by Fabrizia, who developed it with great enthusiasm and autonomy. I think it is important for a young researcher to have a project that she/he truly feels like her/his own”. A real team work, carried out by a multidisciplinary crew composed by groups from the Vita-Salute San Raffaele University, the Italian Institute of Technology (IIT) and the University of Genoa respectively led by Prof. Flavia Valtorta, Fabio Benfenati, and Dr. Silvia Giovedì.

THE APACHE PROTEIN

The gene proposed by Wren gives rise to a protein initially called KIAA1107, an abbreviation soon replaced with APache. “A somewhat fanciful name, chosen because it binds to the AP2 protein [clathrin/adapter protein complex 2, a complex located on the inner membrane of cells that helps the process of vesicle internalization, Editor’s note]”.

The bioinformatics analysis allowed to formulate the hypothesis that the protein was involved in the functioning of the nervous system. Dr. Guarnieri explains: “By studying it with various techniques, we have been able to appreciate how APache is present at the level of synapses [the “contacts” between neurons, Editor’s note], involved in the process of neurotransmitter release and especially in the recovery of the synaptic vesicle [the organelles containing neurotransmitters, Editor’s note] membrane after their release, which is a crucial step to allow the neurotransmitter to be “recycled” and not run out over time. Our work has observed how APache is also involved in the development of neurons, since its loss determines important defects of neuronal growth”. No doubt then that it is fundamental in the development of the nervous system.

Schematic representation of the defects caused by the absence of APache in the synapse: synaptic vesicles containing neurotransmitters (in yellow) are reduced in number, the recovery of their membrane carried out by APache together with the proteins AP2 and clathrin (in red) is impaired and the compartment that acts as a “depot” of synaptic vesicle membranes inside the synapse (i.e., the endosomal compartment, in blue) is much wider than normal. All these defects indicate that the management of synaptic vesicle release is altered in synapses without APache. Kind courtesy of Dr. Guarnieri.
Schematic representation of the defects caused by the absence of APache in the synapse: synaptic vesicles containing neurotransmitters (in yellow) are reduced in number, the recovery of their membrane carried out by APache together with the proteins AP2 and clathrin (in red) is impaired and the compartment that acts as a “depot” of synaptic vesicle membranes inside the synapse (i.e., the endosomal compartment, in blue) is much wider than normal. All these defects indicate that the management of synaptic vesicle release is altered in synapses without APache. Kind courtesy of Dr. Guarnieri.

A MULTIFUNCTIONAL PROTEIN

Most likely the situation is even more complex than that” continues Dr. Guarnieri. “We believe that Apache is a multifunctional protein. As an example, we recently understood that the protein comes in many variants, which may be differentially regulated during the development of the nervous system and may play diverse functions in developing and mature neurons”.

The APache protein visualized in mouse neurons in culture. Kind courtesy of Dr. Guarnieri.
The APache protein visualized in mouse neurons in culture. Kind courtesy of Dr. Guarnieri.

This opens the way to many other studies aimed at understanding the full potential of the protein. One possibility has already been proposed and has recently been financed by a Young Investigator grant from Fondazione Cariplo to Dr. Guarnieri, project leader, and Dr. Giovedì as her partner. “All the information that we collected up to now led us to hypothesize that APache could be relevant in neurodegenerative diseases, such as Alzheimer’s disease – explains Dr. Guarnieri – and we are probably going in the right direction. In fact, patients affected by Alzheimer’s disease show altered levels of APache as compared to healthy individuals”. The project will start in few months and the aim will be to understand the role of APache in those cellular mechanisms whose disfunctioning causes neuronal death and consequently uncurable neurodegenerative diseases.

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