Increased surface P2X4 receptors by mutant SOD1 proteins contribute to ALS pathogenesis in SOD1-G93A mice.

Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron (MN) disease characterized by protein misfolding and aggregation leading to cellular degeneration. So far neither biomarker, nor effective treatment has been found. ATP signaling and P2X4 receptors (P2X4) are upregulated in various neurodegenerative diseases. Here we show that several ALS-related misfolded proteins including mutants of SOD1 or TDP-43 lead to a significant increase in surface P2X4 receptor density and function in vitro. In addition, we demonstrate in the spinal the cord of SOD1-G93A (SOD1) mice that misfolded SOD1-G93A proteins directly interact with endocytic adaptor protein-2 (AP2); thus, acting as negative competitors for the interaction between AP2 and P2X4, impairing constitutive P2X4 endocytosis. The higher P2X4 surface density was particularly observed in peripheral macrophages of SOD1 mice before the onset and during the progression of ALS symptoms positioning P2X4 as a potential early biomarker for ALS. P2X4 expression was also upregulated in spinal microglia of SOD1 mice during ALS and affect microglial inflammatory responses. Importantly, we report using double transgenic SOD1 mice expressing internalization-defective P2X4mCherryIN knock-in gene or invalidated for the P2X4 gene that P2X4 is instrumental for motor symptoms, ALS progression and survival. This study highlights the role of P2X4 in the pathophysiology of ALS and thus its potential for the development of biomarkers and treatments. We also decipher the molecular mechanism by which misfolded proteins related to ALS impact P2X4 trafficking at early pathological stage in cells expressing-P2X4.

Chronic maternal exposure to titanium dioxide nanoparticles alters breathing in newborn offspring.

BACKGROUND: Over the last two decades, nanotechnologies and the use of nanoparticles represent one of the greatest technological advances in many fields of human activity. Particles of titanium dioxide (TiO2) are one of the nanomaterials most frequently found in everyday consumer products. But, due in particular to their extremely small size, TiO2 nanoparticles (NPs) are prone to cross biological barriers and potentially lead to adverse health effects. The presence of TiO2 NPs found in human placentae and in the infant meconium has indicated unequivocally the capacity for a materno-fetal transfer of this nanomaterial. Although chronic exposure to TiO2 NPs during pregnancy is known to induce offspring cognitive deficits associated with neurotoxicity, the impact of a gestational exposure on a vital motor function such as respiration, whose functional emergence occurs during fetal development, remains unknown. RESULTS: Using in vivo whole-body plethysmographic recordings from neonatal mice, we show that a chronic exposure to TiO2 NPs during pregnancy alters the respiratory activity of offspring, characterized by an abnormally elevated rate of breathing. Correspondingly, using ex vivo electrophysiological recordings performed on isolated brainstem-spinal cord preparations of newborn mice and medullary slice preparations containing specific nuclei controlling breathing frequency, we show that the spontaneously generated respiratory-related rhythm is significantly and abnormally accelerated in animals prenatally exposed to TiO2 NPs. Moreover, such a chronic prenatal exposure was found to impair the capacity of respiratory neural circuitry to effectively adjust breathing rates in response to excitatory environmental stimuli such as an increase in ambient temperature. CONCLUSIONS: Our findings thus demonstrate that a maternal exposure to TiO2 NPs during pregnancy affects the normal development and operation of the respiratory centers in progeny.