Anales RANF

S20-04 TARGETING P2X7 IN AMYOTROPHIC LATERAL SCLEROSIS: WHERE AND WHEN? Volonté C. 1, 2 , Fabbrizio P. 1, 2 , Amadio S. 1 , Apolloni S. 1 1 CNR-Institute of Biochemistry and Cell Biology, Rome, IT, 2 IRCCS Fondazione Santa Lucia, Rome , IT Amyotrophic lateral sclerosis (ALS) is a predominant motor neuron disease that irreversibly targets upper and lower motor neurons. Upper motor neurons carry motor information from the motor cortex through the brainstem and spinal cord to the lower motor neurons, which in turn directly signal to the muscles. The loss of somatic motor neurons and their innervation to voluntary skeletal muscles occurring in ALS, leads to paralysis that culminates into respiratory failure and death. In the majority of cases, ALS occurs as a sporadic form, while about 10-15% of patients suffer from a familial disease attributed to dominant, high-penetrance gene variants. More than twenty-five genes have been identified which are responsible for about 60% of familial forms and 10% of sporadic patients. Among the most common genetic mutations known to cause ALS, more than 180 different mutations are located on the SOD1 gene encoding the cytoplasmic enzyme superoxide dismutase 1, found mutated in about 20% of familial patients and 2% of sporadic cases. Although the SOD1- G93A (glycine 93 changed into alanine) is a relatively rare mutation, it is currently expressed in the animal model that best mimics some phenotypic and pathological feature of both familial and sporadic ALS, the SOD1-G93A mouse. The concept that the purinergic P2X7 receptor could become a “key player” in ALS has recently emerged from in vitro and in vivo studies. What we have learned is that precocious genetic ablation of the receptor is certainly detrimental on disease progression, that pharmacological systemic inhibition at pre-symptomatic phase or after disease onset might still be too early or too late to elicit beneficial effects, finally that there is a precise time window of intervention (the late pre-onset) when pharmacological inhibition of the P2X7 provides successful outcomes on motor performance and survival. In other words, there is a precise time dependency concerning the role of P2X7 that likely acts as a dual modifier in ALS disease. In general, whether P2X7 activation is beneficial or detrimental depends on a lot of factors, including the nature and the duration of the toxic insult, and the specific cell population, both converging in a precise temporal window of the injury event. With our studies, we have provided clear evidence that a P2X7-targeted and site-specific modulation might be an additional strategy to interfere with the complex multifactorial and multisystem nature of ALS.