Human inherited neuropathies
Myelin is a multilamellar membrane, which provides electrical insulation around the axon and participates to bidirectional communication with neurons and the extracellular environment. Schwann cells are the myelinating cells in the peripheral nervous system (PNS), which are in a 1 to 1 relationship with the axon to be myelinated. These myelin-forming cells provide to axons trophic support, regulate axonal transport and physiology. On the contrary, axonal signals promote Schwann cell differentiation and myelination during development, control myelin maintenance and homeostasis in the adult and influence the remyelination capacity after injury. Given this strict functional relationship, a defect primarily arising in Schwann cells or in axons/neurons is affecting the physiology of the whole functional unit and provokes human diseases.
Research in our laboratory follows a multidisciplinary approach including genetics, biochemistry and cell biology and seeks to:
- identify new genes in human responsible for inherited peripheral neuropathies and lower motor neuron diseases;
- elucidate how defects in these genes provoke human diseases;
- clarify the molecular mechanisms that regulate membrane trafficking and homeostasis during myelin biogenesis using in vivo and ex vivo models of myelination;
- exploit these mechanisms to design therapeutical strategies to ameliorate PNS diseases.
Bolino A, Piguet F, Alberizzi V, Pellegatta M, Rivellini C, Guerrero-Valero M, Noseda R, Brombin C, Nonis A, D'Adamo P, Taveggia C, Previtali SC. Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination. EMBO Mol Med. 2016 Dec 1;8(12):1438-1454.
Noseda R, Guerrero-Valero M, Alberizzi V, Previtali SC, Sherman DL, Palmisano M, Huganir RL, Nave KA, Cuenda A, Feltri ML, Brophy PJ, Bolino A. SC Kif13b regulates PNS and CNS myelination through the Dlg1 scaffold. PLoS Biol. 2016 Apr 12;14(4):e1002440.
Mironova YA, Lenk GM, Lin JP, Lee SJ, Twiss JL, Vaccari I, Bolino A, Havton LA, Min SH, Abrams CS, Shrager P, Meisler MH, Giger RJ. PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms. Elife. 2016 Mar 23;5. pii: e13023.
Vaccari I, Carbone A, Previtali SC, Mironova YA, Alberizzi V, Noseda R, Rivellini C, Bianchi F, Del Carro U, D'Antonio M, Lenk GM, Wrabetz L, Giger RJ, Meisler MH, Bolino A. Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy. Hum Mol Genet. 2015 Jan 15; 24(2): 383–396.
Noseda R, Belin S, Piguet F, Vaccari I, Scarlino S, Brambilla P, Martinelli Boneschi F, Feltri ML, Wrabetz L, Quattrini A, Feinstein E, Huganir RL, Bolino A. DDIT4/REDD1/RTP801 is a novel negative regulator of Schwann cell myelination. J Neurosci. 2013 Sep 18;33(38):15295-305.
Hnia K, Vaccari I, Bolino A, Laporte J. Myotubularin phosphoinositide phosphatases: cellular functions and disease pathophysiology. Trends Mol Med. 2012 Jun;18(6):317-27.
Vaccari I, Dina G, Tronchère H, Kaufman E, Chicanne G, Cerri F, Wrabetz L, Payrastre B, Quattrini A, Weisman LS, Meisler MH, Bolino A. Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. PLoS Genet. 2011 Oct;7(10):e1002319 .
Benedetti S, Previtali SC, Coviello S, Scarlato M, Cerri F, Di Pierri E, Piantoni L, Spiga I, Fazio R, Riva N, Natali Sora MG, Dacci P, Malaguti MC, Munerati E, Grimaldi LM, Marrosu MG, De Pellegrin M, Ferrari M, Comi G, Quattrini A, Bolino A. Analyzing histopathological features of rare charcot-marie-tooth neuropathies to unravel their pathogenesis. Arch Neurol. 2010 Dec;67(12):1498-505.
Bolino A, Bolis A, Previtali SC, Dina G, Bussini S, Dati G, Amadio S, Del Carro U, Mruk DD, Feltri ML, Cheng CY, Quattrini A, Wrabetz L. Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis. J Cell Biol. 2004 Nov 22;167(4):711-21.
Bolino A, Muglia M, Conforti FL, LeGuern E, Salih MA, Georgiou DM, Christodoulou K, Hausmanowa-Petrusewicz I, Mandich P, Schenone A, Gambardella A, Bono F, Quattrone A, Devoto M, Monaco AP. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet. 2000 May;25(1):17-9.