کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
3069228 1580627 2016 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Dynamin 1 isoform roles in a mouse model of severe childhood epileptic encephalopathy
ترجمه فارسی عنوان
نقش ایزوفرم دینام 1 در یک مدل ماوس از آنسفالوپاتیک صرع شدید دوران کودکی است
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی عصب شناسی
چکیده انگلیسی


• Dnm1 exon 10 is alternatively spliced to produce distinct middle domains.
• The isoforms are differentially trafficked and have distinct protein interactions.
• Each Dnm1 isoform can compensate for the other in normal genotypic conditions
• Dnm1b cannot compensate if challenged by pathogenic Dnm1aFtfl, implying unique isoform function
• The effect of Dnm1Ftfl on splice form abundance does not contribute to its pathology.

Dynamin 1 is a large neuron-specific GTPase involved in the endocytosis and recycling of pre-synaptic membranes and synaptic vesicles. Mutations in the gene encoding dynamin 1 (DNM1) underlie two epileptic encephalopathy syndromes, Lennox-Gastaut Syndrome and Infantile Spasms. Mice homozygous for the Dnm1 “fitful” mutation, a non-synonymous coding variant in an alternatively spliced exon of Dnm1 (exon 10a; isoform designation: Dnm1aFtfl) have an epileptic encephalopathy-like disorder including lethal early onset seizures, locomotor and neurosensory deficits. Although fitful heterozygotes have milder recurrent seizures later in life, suggesting an additive or semi-dominant mechanism, the molecular etiology must also consider the fact that Dnm1aFtfl exerts a dominant negative effect on endocytosis in vitro. Another complication is that the fitful mutation induces alterations in the relative abundance of Dnm1 splice variants; mutants have a downregulation of Dnm1a and an upregulation of Dnm1b, changes which may contribute to the epileptic pathology. To examine whether Dnm1a loss of function, Dnm1aFtfl dominance or compensation by Dnm1b is the most critical for severe seizures, we studied alternate isoform-specific mutant mice. Mice lacking Dnm1 exon 10a or Dnm1 exon 10b have neither spontaneous seizures nor other overt abnormalities, suggesting that in normal conditions the major role of each isoform is redundant. However, in the presence of Dnm1aFtfl only exon 10a deleted mice experience severe seizures. These results reveal functional differences between Dnm1a and Dnm1b isoforms in the presence of a challenge, i.e. toxic Dnm1Ftfl, while reinforcing its effect explicitly in this model of severe pediatric epilepsy.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neurobiology of Disease - Volume 95, November 2016, Pages 1–11
نویسندگان
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