Suppression of agrin‐22 production and synaptic dysfunction in Cln1^−/− mice

Abstract

ObjectiveOxidative stress in the brain is highly prevalent in many neurodegenerative disorders including lysosomal storage disorders, in which neurodegeneration is a devastating manifestation. Despite intense studies, a precise mechanism linking oxidative stress to neuropathology in specific neurodegenerative diseases remains largely unclear.MethodsInfantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease caused by mutations in the ceroid lipofuscinosis neuronal‐1 (CLN1) gene encoding palmitoyl‐protein thioesterase‐1. Previously, we reported that in the brain of Cln1 −/− mice, which mimic INCL, and in postmortem brain tissues from INCL patients, increased oxidative stress is readily detectable. We used molecular, biochemical, immunohistological, and electrophysiological analyses of brain tissues of Cln1 −/− mice to study the role(s) of oxidative stress in mediating neuropathology.ResultsOur results show that in Cln1 −/− mice oxidative stress in the brain via upregulation of the transcription factor, CCAAT/enhancer‐binding protein‐δ, stimulated expression of serpina1, which is an inhibitor of a serine protease, neurotrypsin. Moreover, in the Cln1 −/− mice, suppression of neurotrypsin activity by serpina1 inhibited the cleavage of agrin (a large proteoglycan), which substantially reduced the production of agrin‐22, essential for synaptic homeostasis. Direct whole‐cell recordings at the nerve terminals of Cln1 −/− mice showed inhibition of Ca2+ currents attesting to synaptic dysfunction. Treatment of these mice with a thioesterase‐mimetic small molecule, N‐tert (Butyl) hydroxylamine (NtBuHA), increased agrin‐22 levels.InterpretationOur findings provide insight into a novel pathway linking oxidative stress with synaptic pathology in Cln1 −/− mice and suggest that NtBuHA, which increased agrin‐22 levels, may ameliorate synaptic dysfunction in this devastating neurodegenerative disease.

Integrated Proteomics and Metabolomic Analyses of Plasma Injury Biomarkers in a Serious Brain Trauma Model in Rats

“…Recent studies indicate that Serpina1 is associated with various diseases, such as sporadic amyotrophic lateral sclerosis, cancers, schizophrenia, bipolar disorder, and frontotemporal dementia [ 24 , 25 , 26 , 27 ]. Furthermore, a recent study by Peng et al indicated that up-regulation of Serpina1 could suppress agrin-22 production and eventually lead to synaptic dysfunction [ 28 ]. In the present study, the significantly down-regulated Serpina1 may play an important role in maintaining axonal stabilization post-injury.…”

The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells

“…In this experimental setting, an increased expression of a wild-type CLN1 was functionally linked to DEGs encoding palmitoylated neuronal proteins, pinpointed impaired cellular functions (i.e., neuritogenesis) and coupled with dysregulated expression of synapse-related genes. Affected modules and related functions are associated with the pathological effects related to loss-of-function, and are known to be affected in Ppt1 −/− mice, including pathological changes of a synaptic compartment (Virmani et al, 2005 ; Kielar et al, 2009 ; Peng et al, 2015 ; Tikka et al, 2016 ); moreover a severe epilepsy associated with typical Electroencephalogram (EEG) pattern (Santavuori, 1973 ) occurs in CLN1 patients, who are lacking PPT1 functional activity.…”

Shaping Synapses by the Neural Extracellular Matrix

“…Additional evidence for the potential role of neurotrypsin in synaptic homeostasis comes from a recent study in which it was postulated that synaptic dysfunction found in Cln1−/− mice, a mouse model of infantile neuronal ceroid lipofuscinosis (INCL), could be due to, at least in part, a novel mechanism that links oxidative stress with suppression of agrin 22 production in INCL disease. Interestingly, they showed that treatment with a specific antioxidant, NtBuHA, elevated agrin 22 levels, and therefore, may have therapeutic implications for this devastating disease (Peng et al, 2015 ).…”