Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of polyglutamine repeat within ataxin-1 protein. Cerebellar Purkinje cells are the primary targets of SCA1 pathology. These cells synthesize insulin-like growth factor-I (IGF-I) and express its receptors during their entire life. The aim of present study was to determine if intranasally administered IGF-I to SCA1 transgenic mice suppresses toxic effects of ataxin-1. Two-week old SCA1 heterozygous animals were randomly divided into two treatment groups of IGF-I (30 and 60 microg IGF-I/animal) and a vehicle-treated control group. The wildtype animals served as normal controls. IGF-I or vehicle was administered at 48 h intervals for the total of 10 doses. Animals were then subjected to rotarod test, sacrificed, brains removed and processed for immunohistochemical and Western blot analysis. Radiolabeled IGF-I and bioactive TAT peptide accumulated in the brains of SCA1 mice following intranasal administration validating the use of intranasal route. SCA1 mice showed SCA1 pathology with impaired motor function and downregulation of calcium binding proteins as compared to wildtype mice. However, 30 and 60 microg IGF-I-treated animals showed improved performance on the rotarod as compared to vehicle-treated SCA1 mice with significant improvement (p < 0.05) on day 3 in 60 microg IGF-I group. The immunohistochemical data further showed partial recovery in the expression of calbindin D28k and protein kinase C-gamma in Purkinje cells in IGF-I-treated SCA1 animals. Our results indicate that suppression of ataxin-1-mediated adverse effects by intranasal IGF-I treatment may be of a therapeutic value to treat SCA1.
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PMID:Intranasal administration of IGF-I improves behavior and Purkinje cell pathology in SCA1 mice. 1664 85

Delivery of therapeutic molecules to the brain for the treatment of Neurodegenerative diseases (ND) is a challenging task. This manuscript introduces a novel scheme of synthesizing peptide-tagged polyethylene glycol (PEG)ylated chitosan polymer to develop nanoparticles for siRNA delivery for use in ND. Specifically, this manuscript proposes a facile chemoselective conjugation of monomethoxy PEG, at the C2 hydroxyl group of chitosan polymer, with conjugation of PEG to a cell-penetrating peptide, Trans-Activator of Transcription. The synthesized Chitosan-PEG-TAT polymer was used to form the nanoparticles of approximately 5 nm, complexing siRNA to be delivered in neuronal cells (Neuro 2a), with no/minimal toxicity. The various intermediates and the final product formed during the synthesis were characterized using (1)H Nuclear Magnetic Resonance and Fourier Transform Infrared Spectroscopy spectra. The morphological details of the nanoparticles were studied using Transmission Electron Microscopy. The nanoparticles were tested to deliver a functional siRNA against the Ataxin-1 gene in an in-vitro established model of a ND Spinocerebellar ataxia (SCA1) over-expressing ataxin protein. The results indicate successful suppression of the SCA1 protein following 48 h of transfection. Result of this study has potential in ND like SCA, Parkinson's, Alzheimer's and others.
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PMID:Synthesis of TAT peptide-tagged PEGylated chitosan nanoparticles for siRNA delivery targeting neurodegenerative diseases. 2314 Sep 78