Abstract
‘Tomacula’ and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin-1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P3 at paranodal loops and Schmidt–Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies.
Highlights
Inherited neuropathies, known as Charcot Marie Tooth disease (CMT) or hereditary motor and sensory neuropathies (HMSN), comprise a genetically heterogeneous group of neuromuscular disorders of considerable prevalence (Skre, 1974)
We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies
When we determined the degree of myelination for axons larger than 2 mm in diameter, we found a g-ratio for the Pten mutants (Ptenflox/ floxÃCnpCre/þ) of 0.6345 (Æ0.0094), which is not significantly different from controls (Ptenflox/floxÃCnpþ/þ; 0.6339 Æ 0.0129) (Fig 1B)
Summary
Known as Charcot Marie Tooth disease (CMT) or hereditary motor and sensory neuropathies (HMSN), comprise a genetically heterogeneous group of neuromuscular disorders of considerable prevalence (Skre, 1974). The main clinical features of CMT diseases are a distally accentuated muscle weakness and atrophy, foot deformities and sensory deficits. Mutations in the gene for the myotubularin-related protein-2 (MTMR2), a D3-phosphatase that dephosphorylates both PtdIns(3)P and PtdIns(3,5)P2, underlie the autosomal recessive form CMT-4B1 (Bolino et al, 2000; Bolis et al, 2005; Bonneick et al, 2005; Houlden et al, 2001; Nelis et al, 2002). A similar neuropathy, CMT-4B2, is caused by mutations in the gene for MTMR13/Set-binding factor-2 (SBF2). While this protein is catalytically inactive, it forms a tetrameric complex with MTMR2, thereby strongly increasing that enzyme’s activity www.embomolmed.org
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