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

Autor: Peng S; 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., Xu J; Synaptic Transmission Section (HNQ23-R) National Institute of Neurological Disorders and Stroke NIH Bethesda Maryland 20892., Pelkey KA; The Program in Developmental Neuroscience Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-3715., Chandra G; 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., Zhang Z; 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., Bagh MB; 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., Yuan X; The Program in Developmental Neuroscience Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-3715., Wu LG; Synaptic Transmission Section (HNQ23-R) National Institute of Neurological Disorders and Stroke NIH Bethesda Maryland 20892., McBain CJ; The Program in Developmental Neuroscience Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-3715., Mukherjee AB; 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.
Jazyk: angličtina
Zdroj: Annals of clinical and translational neurology [Ann Clin Transl Neurol] 2015 Nov 06; Vol. 2 (12), pp. 1085-104. Date of Electronic Publication: 2015 Nov 06 (Print Publication: 2015).
DOI: 10.1002/acn3.261
Abstrakt: 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.
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.
Databáze: MEDLINE
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