Active project: PRALS

PRALS

P2X7 Receptor in Amyotrophic Lateral Sclerosis

The Project

 

A pathological hallmark of Amyotrophic Lateral Sclerosis (ALS) is neuroinflammation. Evidence obtained in animal models of the disease indicates a non-cell-autonomous motoneuron death enhanced by nonneuronal cells via an inflammatory response, which accelerates the disease progression. Consistently, analysis of tissues from both familial and sporadic ALS patients reveals a marked microglial-dominated neuroinflammation. Microglia are considered the immune cells of the Central Nervous System, providing the first line of defence whenever injury occurs. They constantly scan the environment and are activated by a wide range of stimuli, often arising from injured surrounding neurons. Among these factors, purine/pyrimidine nucleotides are prominent triggers of microglia activation and play a well established pro-inflammatory role, by binding to ionotropic P2X and metabotropic P2Y purinergic receptors.

Compelling evidence is lately emerging on purinergic receptor involvement in sporadic and familial ALS. Particularly, the P2X7 receptor subtype was found over-expressed in activated microglia from spinal cord of ALS patients. Recent results published by our group indicated an overall potentiation of purinergic signalling in microglia models for ALS, which reflected into augmented inflammatory responses and toxic effects exerted by extracellular nucleotides on motoneurons. By the use of selective purinergic ligands, we also identified the P2X7 receptor subtype as a major effector in exacerbating the neurotoxic action of ALS microglia. On the basis of these results, here we propose to explore a completely novel purinergic strategy that may be successful at intercepting microglia activation and motoneuron damage in ALS and to decode the mechanisms of the neurotoxic actions of this receptor in cellular models of ALS-microglia and ALS-neurons.

In particular, our goal will be to inhibit the P2X7 receptor subtype by genetic and pharmacological manipulation of ALS (hSOD-G93A) mice model and to decode the mechanisms of the neurotoxic actions of this receptor in cellular models of ALS-microglia and ALS-neurons. Since neuroinflammatory events are found in all ALS cases, the results obtained by this study could be easily translated to the great majority of ALS forms which are sporadic in origin. Thus, with the attainment of the expected results, we will: elucidate the role and mechanisms of the noxious P2X7 receptor signalling in ALS; ameliorate the pathologic conditions of ALS in animal models; identify purinergic ligands as possible “druggable” compounds against ALS. These results would become of impact both to the knowledge of the clinical and molecular aspects of purinergic receptors and ALS and to the identification of novel pathways to possibly slow the p  rogression of both familial and sporadic ALS.

The Research team

Principal Investigator:

Nadia D’Ambrosi

Istituto di Neurobiologia e Medicina Molecolare,
Consiglio Nazionale delle Ricerche (CNR)

e-mail:  n.dambrosi@hsantalucia.it

Curriculum and references

Partner 2.

Patrizia Popoli

Research director, Head of section
(Central Nervous System Pharmacology),
Department of Therapeutic  Research and Medicines Evaluation,
Istituto Superiore di Sanità, Roma, Italy.

e-mail: patrizia.popoli@iss.it

Curriculum and references

Project progress

Year 1

Year 2

 

Year 3

 

Supported by: