کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8397413 | 1544163 | 2013 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Effects of enzymatically inactive recombinant botulinum neurotoxin type A at the mouse neuromuscular junctions
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کلمات کلیدی
NMPsendplate currentTSRHRSEDLEPCMNTmEPCBoNT/A - BoNT / AACh - آهNeuromuscular junction - اتصال عصبی عضلانیAcetylcholine - استیل کولینAcetylcholine release - انتشار استیل کولینextensor digitorum longus - اکستانسور بلند شست انگشتانlight chain - زنجیره سبکheavy chain - زنجیره سنگینBotulinum neurotoxin A - نوروتوکسین بوتولینوم AMotor nerve terminals - پایانه های عصبی موتور
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیوشیمی، ژنتیک و زیست شناسی مولکولی (عمومی)
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چکیده انگلیسی
Botulinum neurotoxin A (BoNT/A) is used clinically to treat several neurological and metabolic diseases. However, the mechanisms that underlie the clinical use of the toxin remain still to be elusive. BoNT/A inhibits acetylcholine (ACh) release at the motor nerve terminals (MNT) and causes neuroparalysis. The toxic effects of BoNT/A at the MNT occur in sub-pico molar range, and it is invaluable to determine the half-life and the persistence of catalytic activity of the toxin to develop therapeutics against BoNT/A intoxication. However, the use of extremely low concentrations of BoNT/A in cellular, or animal models due to high toxicity makes it difficult to determine new cellular mechanisms and binding or interacting partners of BoNT/A. In order to address this, a catalytically deactivated, non-toxic version of BoNT/A, designated as DrBoNT/A, was characterized. DrBoNT/A lacks endoprotease activity (SNAP-25 cleavage) at concentrations as high as 46,875 - fold, compared to wild-type BoNT/A. Unlike BoNT/A injection (3.2 pg), injection of the recombinant product (150 ng or 3.2 pg) into mouse hind limbs failed to cause neuroparalysis as exhibited by the lack of inhibition of toe spread reflex (ability of the mouse to spread its hindlimb toes), and inhibit ACh release at the MNT. The in vitro experiments also demonstrate that DrBoNT/A uptake (at concentrations equivalent to BoNT/A), internalization and localization at the MNT remained unaltered. In addition, modeling studies support that DrBoNT/A lacked the zinc binding ability, and the ability to directly participate in the hydrolysis of SNAP-25 substrate. Collectively, we demonstrate that DrBoNT/A is non-toxic to the MNT and can be used as a surrogate tool to understand the mechanism by which BoNT/A modulates signal transduction mechanisms.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicon - Volume 72, 15 September 2013, Pages 71-80
Journal: Toxicon - Volume 72, 15 September 2013, Pages 71-80
نویسندگان
Padmamalini Baskaran, Teresa E. Lehmann, Elena Topchiy, Nagarajan Thirunavukkarasu, Shuowei Cai, Bal Ram Singh, Sharad Deshpande, Baskaran Thyagarajan,