: Connexin 32 (Cx32) belongs to a gene family of at least 15 members (in mammals), all of which encode gap junction proteins. Six connexins oligomerize to form a hemi-channel (or connexon), which forms a channel when apposed to another hemi-channel on an adjacent membrane. Gap junctions allow the diffusion of ions and small molecules, typically with a molecular mass less than 1000 Da. Individual hemichannels can be composed of more than one connexin (heterotypic connexons), and hemichannels composed of different connexins can also form channels (heterotypic gap junctions). In a series of papers, my colleagues and I have investigated how mutations in the human Cx32 gene cause the X-linked form of Charcot-Marie-Tooth disease (CMTX). This is the second most common form of inherited demyelinating neuropathy (CMT type 1), a genetically heterogenous group that collectively is among the most common inherited neurological diseases. We were the first to show that mutations cause CMTX, that Cx32 is localized to incisures and paranodes (regions of the Schwann cell (SC) myelin sheath that are composed on non-compact myelin) and that the SC myelin sheath contains functional gap junctions. Of particular relevance to this grant, some mutations result in loss of the protein, or alter trafficking so that the mutant protein does not reach the cell membrane. Of the mutants that reach the cell membrane, some fail to form functional gap junctions (communication-incompetent), whereas others are communication-competent. We have made transgenic mice that express wild type or two different mutant Cx32 alleles and found that trafficking of the two mutant proteins was similar to that in transfected cells. One of the mutants, Arg142Trp, has a dominant-negative effect on wild type Cx32: not only does the mutant protein """"""""hang up"""""""" in the Golgi, it also causes the wild type protein to accumulate there, too. The goals of this competing renewal are as follows: (1) to determine whether the effects of CMTX mutations are autonomous to myelinating Schwann cells; (2) to determine how Cx32 mutants that form gap junctions in vitro disrupt the function of myelinating SC; (3) to determine whether myelinating SC express other connexins and whether other connnexins can substitute for Cx32 in myelinating SC. The results will elucidate how gap junction proteins are assembled and function in myelinating SC, provide fundamental information on the molecular pathophysiology of CMTX, and illuminate how mutations in other gap junction proteins cause disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042878-02
Application #
6620916
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Nichols, Paul L
Project Start
2001-12-15
Project End
2006-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
2
Fiscal Year
2003
Total Cost
$376,438
Indirect Cost
Name
University of Pennsylvania
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wasseff, Sameh K; Scherer, Steven S (2015) Activated immune response in an inherited leukodystrophy disease caused by the loss of oligodendrocyte gap junctions. Neurobiol Dis 82:86-98
Wasseff, Sameh; Abrams, Charles K; Scherer, Steven S (2010) A dominant connexin43 mutant does not have dominant effects on gap junction coupling in astrocytes. Neuron Glia Biol 6:213-23
Ahn, Meejin; Lee, Jonathan; Gustafsson, Andreas et al. (2008) Cx29 and Cx32, two connexins expressed by myelinating glia, do not interact and are functionally distinct. J Neurosci Res 86:992-1006
Sargiannidou, Irene; Ahn, Meejin; Enriquez, Alan D et al. (2008) Human oligodendrocytes express Cx31.3: function and interactions with Cx32 mutants. Neurobiol Dis 30:221-33
Orthmann-Murphy, Jennifer L; Enriquez, Alan D; Abrams, Charles K et al. (2007) Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease. Mol Cell Neurosci 34:629-41
Huang, Yan; Grinspan, Judith B; Abrams, Charles K et al. (2007) Pannexin1 is expressed by neurons and glia but does not form functional gap junctions. Glia 55:46-56
Yum, Sabrina W; Zhang, Junxian; Valiunas, Virginijus et al. (2007) Human connexin26 and connexin30 form functional heteromeric and heterotypic channels. Am J Physiol Cell Physiol 293:C1032-48
Menichella, Daniela M; Majdan, Marta; Awatramani, Rajeshwar et al. (2006) Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity. J Neurosci 26:10984-91
Jeng, Linda Jo Bone; Balice-Gordon, Rita J; Messing, Albee et al. (2006) The effects of a dominant connexin32 mutant in myelinating Schwann cells. Mol Cell Neurosci 32:283-98
Scherer, Steven S; Xu, Yi-Tian; Messing, Albee et al. (2005) Transgenic expression of human connexin32 in myelinating Schwann cells prevents demyelination in connexin32-null mice. J Neurosci 25:1550-9

Showing the most recent 10 out of 18 publications