A10 NAPDH oxidases (NOXs) exocytosis and its relevance in huntington’s disease (HD) pathology

Abstract

Huntington’s disease (HD) is an inherited, neurodegenerative disease (NDD) caused by a poly-glutamine expansion in the mutant Huntingtin (mHtt) protein. Neurodegeneration is a prominent feature in HD pathogenesis and most probably, neuron death itself is preceded by an initial neuronal dysfunction. NADPH oxidases (NOXs) belong to a family of transmembrane enzyme complexes producing Reactive Oxygen Species (ROS). NOXs are expressed in neurons in the CNS and play numerous roles in the regulation of neurodevelopment, neurite growth and synaptic plasticity. Even though impairment of these same processes has been shown in HD, very little is known about the role of NOXs in HD pathogenesis. Our group has shown a cell mechanism where NOXs are secreted into the extracellular space through exosomes. The exact biological function of the latter is still not fully elucidated, but it may have a role in the control of neurites growth and retraction. Indeed, specific NOX complexes are expressed differentially in neurons during differentiation, with opposing roles: NOX2 stimulates initial neurite outgrowth and NOX1 is essential for terminal neuronal differentiation. Huntingtin may regulate or impair NOX sorting into exosomes, since we have shown a differential exocytotic pattern when comparing healthy versus pathogenic HD cell models.