Die Effekte des Wlds-Gens und der Gabe von Nikotinamid auf akute und chronisch-sekundäre Axon-Degeneration

The effects of the Wlds-Gene and the administration of nicotinamide on acute and chronic axonal degeneration

by Timo Miesbach
Doctoral thesis
Date of Examination:2021-07-21
Date of issue:2021-07-21
Advisor:Prof. Dr. Michael Werner Sereda
Referee:Prof. Dr. Michael Werner Sereda
Referee:Prof. Dr. Swen Hülsmann
Referee:Prof. Dr. Jutta Gärtner
Referee:Prof. Dr. Margarete Schön
Referee:Prof. Dr. Wolfgang Brück
Persistent Address: http://dx.doi.org/10.53846/goediss-8730

 

 

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Abstract

English

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and a duplication of the peripheral myelin protein of 22 kDa (PMP22) gene causes the most frequent subform CMT1A. Clinical impairments are determined by the amount of axonal loss. Axons of the spontaneous mouse mutant Wallerian degeneration slow (Wlds) show markedly reduced degeneration following various types of injuries. Protection is conferred by a chimeric Wlds gene encoding an N-terminal part of ubiquitination factor Ube4b and full length nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1). Nmnat1 enzyme generates nicotinamide adenine dinucleotide (NAD) from nicotinamide mononucleotide. Here, in a Pmp22 transgenic animal model of Charcot-Marie-Tooth disease type 1A (CMT rat), the Wlds transgene reduced axonal loss and clinical impairments without altering demyelination. Furthermore, nicotinamide – substrate precursor of the Nmnat1 enzyme – transiently delayed posttraumatic axonal degeneration in an in vivo model of acute peripheral nerve injury, but to a lower extent than Wlds. In contrast, 8 weeks of nicotinamide treatment did not influence axonal loss or clinical manifestations in the CMT rat. Therefore, nicotinamide can partially substitute for the protective Wlds effect in acute traumatic, but not in chronic secondary axonal injury. Future studies are needed to develop axon protective therapy in CMT1A which may be combined with therapeutic strategies aimed at downregulation of toxic PMP22 overexpression.
Keywords: axon degeneration; nicotinamide; Wlds; Wallerian degeneration slow; hereditary neuropathy; CMT1A; traumatic nerve injury

German

Es ließ sich in dieser Arbeit zeigen, dass die Expression des Wlds-Gens im CMT-Modelltier den klinischen Phänotyp der Erkrankung durch Erhaltung von mehr Axonen im peripheren Nerv abschwächt. Eine ähnliche bessere Resistenz von Wlds-Axonen gegen akuten axonalen Schaden konnte ebenfalls nachgewiesen werden. Dieser bestand, weniger stark ausgeprägt, auch nach Zugabe von NaM, der bioverfügbaren Substratvorstufe des NMNAT1-Enzyms. Eine Nutzbarmachung dieses Effekts bei chronisch-sekundärem axonalen Schaden durch externe Zufuhr von NaM im Modelltier der chronischen CMT-Neuropathie gelang jedoch nicht.
Schlagwörter: Axon-Degeneration; Wlds-Gen; Charcot-Marie-Tooth; Neuropathie; Nervenschädigung; Nikotinamid
 
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