Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy

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.

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

“…Only the oldest patient with PTEN-ASD (age 25 years) in our cohort did not show an elevated volume of white matter hypointensities relative to idiopathic ASD and controls [26]. This pattern suggests abnormal development of myelination, possibly consistent with unraveling myelin in Pten mouse models, rather than progressive deterioration [26,28,29]. Diffusion tensor imaging studies are needed to characterize these white matter abnormalities carefully.…”

Myelination and mTOR

“…Inhibition of mTORC1 with rapamycin or improved analogues, an approach already used successfully in cardiology and transplantation medicine (Benjamin, Colombi, Moroni, & Hall, 2011), could curb excessive myelin growth and myelin aberrations that occur in a number of hereditary neuropathies (Suter & Scherer, 2003). Indeed, rapamycin treatment was able to correct exuberant myelin growth in a mouse model of tomaculous neuropathy (Goebbels et al, 2012). A reduction in mTORC1 activity may also underlie the proposed beneficial effect of inhibiting neuregulin‐1 (NRG1) type III signaling in similar neuropathy models (Bolino et al, 2016), although the role of NRG1 signaling in neuropathies is complex (Fledrich et al, 2014).…”

“…The major outcomes of the loss‐ and gain‐of‐function studies on the roles of mTORC1 and the upstream PI3K‐Akt and Mek‐Erk1/2 pathways in PNS and CNS myelination are summarized (Beirowski et al, 2017; Bercury et al, 2014; Carson et al, 2015; Cotter et al, 2010; Domenech‐Estevez et al, 2016; Figlia et al, 2017; Flores et al, 2008; Fyffe‐Maricich, Karlo, Landreth, & Miller, 2011; Fyffe‐Maricich, Schott, Karl, Krasno, & Miller, 2013; Goebbels et al, 2010, 2012; Ishii, Furusho, & Bansal, 2013; Ishii, Furusho, Dupree, & Bansal, 2016; Jeffries et al, 2016; Jiang et al, 2016; Lebrun‐Julien et al, 2014; Napoli et al, 2012; Newbern et al, 2011; Norrmén et al, 2014; Sheean et al, 2014; Sherman et al, 2012; Wahl et al, 2014; Zou et al, 2011, 2014)…”

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

“…This leads to mild hypermyelination of small peripheral axons, and to locally restricted hypermyelination close to the nodes of Ranvier (Goebbels et al, 2010;Goebbels et al, 2012).…”