From pathogenic mechanisms of MPZ mutations to peripheral nerve regeneration: Experimental models and clinical perspectives


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A Master's thesis.
From pathogenic mechanisms of MPZ mutations to peripheral nerve regeneration: Experimental models and clinical perspectives
Salerno Alexander
Schenone Angelo
Haastert-Talini Kirsten
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Institut d'Etudes Supérieurs de l'Université de Gênes (IANUA-ISSUGE)
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MD thesis
BACKGROUND : Charcot-Marie-Tooth disease (CMT) defines a large group of hereditary motor and sensor neuropathies. With an overall prevalence of approximately 1:2500, CMT is the most common inherited neuromuscular disorder. The disease can be classified according to pathophysiology and inheritance patterns. The most common form is CMT disease type 1, which is a demyelinating polyneuropathy, followed by CMT type 2, which is an axonal polyneuropathy. Both are autosomal dominant disorders. Mutations that affect myelin protein zero (P0) determine the CMT1B (demyelinating) or CMT2J (axonal) forms of the disease. Generally, mutations that impair the adhesive function of P0 determine a severe, early-onset neuropathy, whereas mutations that affect the signalling function are associated with milder, late-onset disease.
MATERIALS AND METHODS : The study consists of two preclinical phases: an in vitro study of P0-P70S mutation and an in vivo study aimed at studying the impact of P0 protein on peripheral nerve regeneration in vivo.
RESULTS : With regard to the in vitro phase of the study, we have shown that HeLa cells transiently transfected to express P0-P70S are able to express the mutated protein on the surface membrane. Furthermore, adhesion assays evidenced how such mutation determines an important impairment of P0’s adhesive function. As regards the in vivo experimental studies, we have developed a method to deepen the understanding of the peripheral nerve regeneration process.
CONCLUSIONS : Although P0-P70S mutant protein totally reaches the surface membrane and does not show any impairment of the intracellular trafficking, it causes a relevant impairment of the adhesive properties of P0 protein. This represents an uncommon feature if related to the fact that such a mutation causes a late onset disease.
According to literature, it seems that a P0 deficiency would negatively affect the process of peripheral nerve regeneration by significantly delaying the regenerative process. We are therefore planning a set of experiments in order to evaluate the role of such protein in the knock out murine model of CMT1B disease by studying the P0 deficient and eventually the P0 mutated mice.
MD thesis, MD, neurology
Create date
14/07/2022 17:02
Last modification date
15/07/2022 6:36
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