Suppression of agrin-22 production and synaptic dysfunction in Cln1-/- mice

Shiyong Peng, Jianhua Xu, Kenneth A. Pelkey, Goutam Chandra, Zhongjian Zhang, Maria B. Bagh, Xiaoqing Yuan, Ling Gang Wu, Chris J. Mcbain, Anil B. Mukherjee

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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 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. Interpretation: 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.

Original languageEnglish (US)
Pages (from-to)1085-1104
Number of pages20
JournalAnnals of Clinical and Translational Neurology
Issue number12
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology


Dive into the research topics of 'Suppression of agrin-22 production and synaptic dysfunction in Cln1-/- mice'. Together they form a unique fingerprint.

Cite this