Alteration of gap junction protein, Connexin43 in Mouse Hepatitis Virus induced astrogliosis

Vineeth, A. R. (2018) Alteration of gap junction protein, Connexin43 in Mouse Hepatitis Virus induced astrogliosis. Masters thesis, Indian Institute of Science Education and Research Kolkata.

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Abstract

Gap junction intercellular communication mediated by Connexin (Cx) proteins have an essential role in development, differentiation, functional coordination and maintenance of cellular homeostasis. Connexins form a continuous channel connecting the cytoplasm of adjacent cells, called a gap junction channel (GJC), and enable cellular communication through direct transfer of small molecules and ions. Functional alterations in connexins are associated with various human diseases such as Pelizaeus-Merzbacher-like disease (PMLD) and Charcot-Marie-Tooth disease (CMTX). GJC mediated molecular exchange has a crucial role in the Central Nervous System(CNS). Glial cell network formed by major astrocyte and oligodendrocyte connexin isoforms, Cx43 and Cx47 respectively, can influence CNS myelination and homeostasis by regulating the concentration of ions, metabolites, and neurotransmitters. The emerging role of connexins in the CNS further suggests their involvement in various other neurodegenerative diseases such as Multiple Sclerosis (MS). MS is a chronic inflammatory demyelinating disease of the CNS characterized by inflammation, demyelination, and neurodegeneration. Mouse Hepatitis Virus (MHV)-induced demyelinating encephalomyelitis is a major experimental animal model which is capable of providing information on MS etiology in humans. Intracranial or intranasal infection of susceptible mouse strains with neurovirulent strains of MHV, such as MHV-A59 is capable of causing neuropathological alterations comprising of two phases, an acute virus-induced panencephalitis, and a chronic demyelination. Recent studies have shown that Cx43 expression is downregulated due to MHV-A59 infection in the acute stage (5 dpi) and replenishes to normal level by 30 dpi. Its coupling partner, Cx47 showed a persistent downregulation in MHV-A59 infected mice brain, i.e. both in the acute (5 dpi) and chronic phase (30 dpi). Along with the loss of Cx47, an associated loss of myelin marker PLP was observed in the chronic stage, providing insights into the demyelinating pathology observed in this model. Even though, the level of Cx43 returns to normal level by 30 dpi, the depletion of Cx47 may still be persisting, contributing to the progression of myelin loss and degeneration.

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