title: Suppression of agrin-22 production and synaptic dysfunction in Cln1 (-/-) mice.
abstract: OBJECTIVE
  Oxidative 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.
  
  
  METHODS
  Infantile 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.
  
  
  RESULTS
  Our 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 Ca(2+) currents attesting to synaptic dysfunction. Treatment of these mice with a thioesterase-mimetic small molecule, N-tert (Butyl) hydroxylamine (NtBuHA), increased agrin-22 levels.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-1830.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Peng
authors.affiliation: Synaptic Transmission Section (HNQ23-R) National Institute of Neurological Disorders and Stroke NIH Bethesda Maryland 20892.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xu
authors.affiliation: The Program in Developmental Neuroscience Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-3715.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Pelkey
authors.affiliation: Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-1830.
authors.forename: Goutam
authors.initials: G
authors.lastname: Chandra
authors.affiliation: Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-1830.
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-1830.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Bagh
authors.affiliation: The Program in Developmental Neuroscience Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-3715.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Synaptic Transmission Section (HNQ23-R) National Institute of Neurological Disorders and Stroke NIH Bethesda Maryland 20892.
authors.forename: Ling-Gang
authors.initials: LG
authors.lastname: Wu
authors.affiliation: The Program in Developmental Neuroscience Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-3715.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: McBain
authors.affiliation: Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-1830.
authors.forename: Anil B
authors.initials: AB
authors.lastname: Mukherjee