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Review
. 2018 Oct;15(4):966-975.
doi: 10.1007/s13311-018-00686-0.

Dynamin 2 (DNM2) as Cause of, and Modifier for, Human Neuromuscular Disease

Mo Zhao  1 , Nika Maani  1 , James J Dowling  2   3   4   5
Affiliations
Review

Dynamin 2 (DNM2) as Cause of, and Modifier for, Human Neuromuscular Disease

Mo Zhao et al. Neurotherapeutics. 2018 Oct.

Abstract

Dynamin 2 (DNM2) belongs to a family of large GTPases that are well known for mediating membrane fission by oligomerizing at the neck of membrane invaginations. Autosomal dominant mutations in the ubiquitously expressed DNM2 cause 2 discrete neuromuscular diseases: autosomal dominant centronuclear myopathy (ADCNM) and dominant intermediate Charcot-Marie-Tooth neuropathy (CMT). CNM and CMT mutations may affect DNM2 in distinct manners: CNM mutations may cause protein hyperactivity with elevated GTPase and fission activities, while CMT mutations could impair DNM2 lipid binding and activity. DNM2 is also a modifier of the X-linked and autosomal recessive forms of CNM, as DNM2 protein levels are upregulated in animal models and patient muscle samples. Strikingly, reducing DNM2 has been shown to revert muscle phenotypes in preclinical models of CNM. As DNM2 emerges as the key player in CNM pathogenesis, the role(s) of DNM2 in skeletal muscle remains unclear. This review aims to provide insights into potential pathomechanisms related to DNM2-CNM mutations, and discuss exciting outcomes of current and future therapeutic approaches targeting DNM2 hyperactivity.

Keywords: Centronuclear myopathy; Charcot–Marie–Tooth neuropathy; Congenital neuromuscular disorders; DNM2; Gene therapy.

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Figures

Fig. 1
Fig. 1
Schematic diagram of the neuromuscular junction, the triad (1 T-tubule and 2 SRs), and the sarcomere during excitation–contraction coupling in skeletal muscle. The nerve impulse arrives at the synapse that transmits and induces membrane depolarization to the sarcolemma and the T-tubules. The DHPR receptor (blue) on the T-tubule binds to the Ryr1 receptor (orange) on SR membranes, and upon activation triggers Ryr1-regulated release of calcium ions (black dots) from the SR. Subsequent binding of calcium ions to the sarcomeric thin filaments triggers sarcomeric contraction. DNM2 is in proximity to the T-tubule (potentially around the neck of the T-tubules) and SR, while its exact subcellular localization remains unclear (DNM2? in green). Adobe Illustrator CS6 was used to create this diagram
Fig. 2
Fig. 2
Dynamin domain organization, DNM2 disease mutations, and its oligomerization/disassembly process in healthy and disease states. (a) Dynamin consists of 5 domains: an N-terminal GTPase or G domain (yellow), a middle domain (blue), a pleckstrin homology (PH) domain (green), a GTPase effector domain (GED, blue), and a C-terminal proline/arginine-rich domain (PRD, gray). The bundle signaling element (BSE, bright red) is located at the N- and C-termini of the G domain and at the C-terminus of GED. Mutations in DNM2 cluster at the stalk (middle domain and GED, blue) and PH domain, and cause either centronuclear myopathy (top, light red) or Charcot–Marie–Tooth neuropathy (bottom). Mutations that cause early-onset CNM are located at or nearby the PH-GED linker region, i.e., A618D/T, S619L/W, L621P, V625del, and P627H. (b) In the healthy state, dynamin first forms dimers and then further oligomerizes upon lipid-membrane binding. GA and GB are used to label adjacent dimers in a DNM2 polymer. Temporal and spatial control of dynamin oligomerization is mediated by the PH region. The PH domain autoinhibits the stalk to ensure lipid binding occurs before oligomerization. Membrane fission and DNM2 disassembly are then mediated by GTP hydrolysis. (c) In CNM models that carry DNM2 mutations at the stalk/PH region (red crosses), the observed elevated GTPase activity as well as membrane fission (i.e., DNM2 hyperactivity) might be a result of a dysregulated assembly/disassembly process indicated by (1) the formation of more stable oligomers upon lipid binding (e.g., R465W, A168T), i.e., disrupted disassembly; (2) conducting GTPase activity and membrane fission at a higher rate (lipid-sensitized) (e.g., A618T), i.e., more efficient GTP hydrolysis; and/or (3) reaching full GTPase activity without lipid binding (lipid-uncoupled) (e.g., S619L/W), i.e., loss of spatial control over oligomerization. (d) In contrast, CMT models that carry mutations mainly at the lipid-binding PH domain (light blue crosses) have shown impaired lipid binding. As lipid binding is required for oligomerization, predictably less DNM2 oligomers will be present at the membrane and thus the mildly impaired membrane fission activity (i.e., DNM2 hypoactivity) observed in CMT models. Adobe Illustrator CS6 and IBS (Illustrator for Biological Sequences) were used to generate this diagram
Fig. 3
Fig. 3
Potential membrane trafficking events disrupted in DNM2 centronuclear myopathy. (1) DNM2 (green dots) regulates membrane fission during endocytic vesicle release by binding around the neck of either clathrin- or caveolae-coated pits. Impaired endocytosis has been observed in cells expressing CNM-DNM2. (2) The triad [T-tubules (T) and sarcoplasmic reticulum (SR)] is a system of membrane invaginations that regulate EC coupling in muscle. DNM2 is localized in proximity to the triad, while its exact subcellular localization is unknown. However, DNM2 can bind to BIN1 (orange dots) at the T-tubules, another CNM protein that regulates tubulogenesis. BIN1 is localized to the tubular portion of T-tubules, while CAV3 (yellow triangles) is localized to the vesicular ends. While the steps of T-tubule biogenesis remain a debate, the interplay between MTM1 (red dots), BIN1, and DNM2 has been shown to be important for triad biogenesis and/or maintenance. Hyperactivity of DNM2 (e.g., caused by some CNM mutations) can lead to severe fragmentation of T-tubules. (3) DNM2 can either directly bind to cytoskeletal actin (blue lines) to promote actin polymerization, or regulates actin dynamics via binding to BIN1, which binds to cytoskeletal actin via its BAR domain. Actin dynamics is involved in tubulogenesis and myonuclei positioning in cells, and can be disturbed by some CNM mutations. (4) DNM2 can also regulate the maturation of phagophore to autophagosome during autophagy by retrieving Atg9 after Atg9-regulated membrane addition onto phagophores. This may explain the autophagic blockage observed in some CNM models. Adobe Illustrator CS6 was used to create this diagram
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References

    1. Dowling JJ, Lawlor MW, Dirksen RT. Triadopathies: an emerging class of skeletal muscle diseases. Neurotherapeutics. 2014;11(4):773–85. doi: 10.1007/s13311-014-0300-3. - DOI - PMC - PubMed
    1. Al-Qusairi L, Laporte J. T-tubule biogenesis and triad formation in skeletal muscle and implication in human diseases. Skelet Muscle. 2011;1(1):26. doi: 10.1186/2044-5040-1-26. - DOI - PMC - PubMed
    1. Flucher BE, Terasaki M, Chin HM, Beeler TJ, Daniels MP. Biogenesis of transverse tubules in skeletal muscle in vitro. Dev Biol. 1991;145(1):77–90. doi: 10.1016/0012-1606(91)90214-N. - DOI - PubMed
    1. Yuan SH, Arnold W, Jorgensen AO. Biogenesis of transverse tubules and triads: immunolocalization of the 1,4-dihydropyridine receptor, TS28, and the ryanodine receptor in rabbit skeletal muscle developing in situ. J Cell Biol. 1991;112(2):289–301. doi: 10.1083/jcb.112.2.289. - DOI - PMC - PubMed
    1. Takekura H, Flucher BE, Franzini-Armstrong C. Sequential docking, molecular differentiation, and positioning of T-Tubule/SR junctions in developing mouse skeletal muscle. Dev Biol. 2001;239(2):204–14. doi: 10.1006/dbio.2001.0437. - DOI - PubMed

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