TY - JOUR
T1 - Suppression of agrin-22 production and synaptic dysfunction in Cln1-/- mice
AU - Peng, Shiyong
AU - Xu, Jianhua
AU - Pelkey, Kenneth A.
AU - Chandra, Goutam
AU - Zhang, Zhongjian
AU - Bagh, Maria B.
AU - Yuan, Xiaoqing
AU - Wu, Ling Gang
AU - Mcbain, Chris J.
AU - Mukherjee, Anil B.
N1 - Publisher Copyright:
© 2015 American Neurological Association.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
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U2 - 10.1002/acn3.261
DO - 10.1002/acn3.261
M3 - Article
AN - SCOPUS:85009104610
SN - 2328-9503
VL - 2
SP - 1085
EP - 1104
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
IS - 12
ER -