Einfluss von Rapamycin auf Myelinmissbildungen in einem Mausmodel einer tomakulösen Neuropathie

Abstract

Tomacula and other forms of focally folded myelin are striking neuropathological features of a diverse group of demyelinating neuropathies, including Charcot-Marie-Tooth (CMT) 4B, CMT4F, CMT1B and hereditary neuropathy with liability to pressure palsies (HNPP). Despite major progress in defining the genetic basis of these diseases, the molecular mechanisms that cause focal myelin growth and disrupt Schwann cell-axon interaction in some forms of CMT, but not in others, have remained obscure. We have hypothesized that myelin outfolings and "tomacula" result from uncontrolled, excessive myelin membrane growth, a process that is at least in part controlled by neuregulin-1/ErbB2 and PI3K signaling. We have previously shown in mice lacking PTEN expression in Schwann cells, that glial cell-specific hyperactivation of the endogenous PI3K pathway causes focal hypermyelination, myelin outfoldings, and “tomacula”. We found activated AKT kinase associated with phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3, PIP3) at paranodal loops and Schmidt-Lanterman incisures. This and the focal hypermyelination pathology indicate that regions of non-compact myelin permit membrane incorporation and myelin growth, which is strictly controlled by PTEN. Here, we investigated the influence of the specific mTOR-inhibitior rapamycin on the pathological myelin abnormalities in conditional PTEN mutants. Interestingly the results indicate, that the development of tomacula and myelin outfoldings is strictly dependent on AKT/mTOR signaling as evidenced by a significant amelioration of the pathology after rapamycin administration. We suggest a model where elevated PIP3 levels contribute to the pathology of tomaculous neuropathies. However, whether rapamycin would have a beneficial impact in mouse models that resemble human tomaculous neuropathies like HNPP, is still unclear and will be investigated in future experiments.