Fledrich, Robert

A duplication of the gene encoding the peripheral myelin protein 22kDa (PMP22) underlies the commonest inherited neuropathy, Charcot Marie Tooth disease 1A (CMT1A). Although demyelination is a characteristic disease feature, the clinical impairment of CMT1A patients is determined by the extent of axonal loss. Patients suffer from slowly progressive, distally pronounced muscle atrophy and sensory impairments. A therapy is not available yet.
In the present doctoral thesis it is shown that, with the help of Pmp22 transgenic rodent models for CMT1A, Pmp22 overexpressing Schwann cells acquire a persistent dedifferentiation phenotype already during early postnatal development which is similar to Schwann cell dedifferentiation after acute nerve injury. In contrast to nerve lesion, dedifferentiation in Pmp22 overexpressing Schwann cells is triggered by an imbalanced activity of the PI3K/AKT and MEK/ERK signaling pathways. A common feature of both models, however, is a de novo expression of Neuregulin-1 type I in Schwann cells.
With the help of conditional knock-out mice without Neuregulin-1 in Schwann cells, it is demonstrated that the Neuregulin-1 type I expression in Schwann cells after acute nerve injury is essential for proper regeneration. Also Pmp22 transgenic mice without Schwann cell-Neuregulin-1 showed an impairment of the neuropathic phenotype. Vice versa, the experimental reinforcement of Neuregulin-1 signaling by axonal overexpression lead to an improvement of various disease features in CMT1A mice.
In a preclinical experimental therapeutic approach with recombinant Neuregulin-1 in Pmp22 transgenic rats during early postnatal development, almost diminished impaired Schwann cell differentiation and improved nerve function until adulthood.
These data suggest that proper Schwann cell differentiation within a limited postnatal time window is crucial for long-term axonal support

The Role of Neuregulin-1 in Peripheral Nerve Disorders

Abstract

Similar works

Full text

Available Versions

Georg-August-University Göttingen