An early impact of ER stress, inflammation and oxidative stress in the CLN8mnd mouse model of neuronal ceroid lipofuscinosis

e CLN8mnd or mnd (motor neuron degeneration) mouse is a naturally-occurring model of the CLN8- associated late-infantile form of neuronal ceroid lipofuscinoses (NCLs). e NCLs are a group of lysosomal neurodegenerative diseases characterized by epilepsy, progressive motor and cognitive decline, blindness, and by the lysosomal accumulation of autofluorescent lipopigment. e CLN8mnd carries a frameshift mutation in the CLN8 gene, likely encoding a truncated protein at the endoplasmic reticulum (ER), and exhibits premature-onset retinopathy and adult-onset neurological and behavioural dysfunctions such as hyperactivity, aggressiveness, epileptic-like repetitive brain activity, cognitive deficit, mild ataxia and hind limb clutching progressing to severe spastic paralysis. e typical autofluorescent inclusions staining positive for the mitochondrial ATP synthase subunit c appear far before the development of mnd symptoms. e pathomechanisms of mnd disease as well as NCLs' diseases remain still unclear. We and others have demonstrated that changes in calcium levels, mitochondrial energy and lipid metabolism as well as the involvement of oxidative stress together with the formation of lipid peroxides and HNE-adducts occur in the progression of the mnd disease. By analyzing the ER-stress pathways in the mnd mice at the presymptomatic state, we observed that ER-stress responses differed within the CNS regions. However, all the mnd structures exhibited the typical autofluorescent inclusions and developed inflammatory responses integrated with ER-stress pathways. We here show that very early TNF-alpha-mediated responses and changes in the oxidative state, as detected by the ER oxidoreductin (ERO1alpha), may affect the autophagylysosomal degradation machinery