Borna virus again: disruption of GABA leads to anxiety and hyperactivity

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J Virol. 2008 Sep 24. [Epub ahead of print]

Borna

disease virus P protein affects neural transmission through interacting

with gamma-aminobutyric acid receptor-associated protein.

Peng G, ... ate

Key Laboratory of Virology, College of Life Sciences, Wuhan University,

Wuhan 430072, P.R. China; College of Basic Medical Science, Harbin

Medical University, Harbin 150081, P.R. China.

Borna

disease virus (BDV) is one of the infectious agents causing diseases of

central nervous system (CNS) in a wide range of vertebrate species and

perhaps in human. The phosphoprotein (P) of BDV, an essential cofactor

of viral RNA-dependent RNA polymerase, is required for the virus

replication. In this study, we identified the gamma-aminobutyric acid

receptor-associated protein (GABARAP) with functions in neurobiology as

one of the viral P protein-interacting cellular factors by using an

approach of phage display-based protein-protein interaction analysis.

Direct binding between GABARAP and P protein was confirmed by

co-immunoprecipitation, protein pull-down, and mammalian two-hybrid

analyses. GABARAP is originally identified as a linker between

gamma-aminobutyric acid receptor (GABAR) and microtubule to regulate

receptor trafficking and plays importantly roles in the regulation of

the inhibitory neural transmitter, gamma-aminobutyric acid (GABA). We

showed that GABARAP co-localizes with P protein in the cells infected

with BDV or transfected with the P gene, which resulted in shifting the

localization of GABARAP from cytosol to nucleus. We further

demonstrated that P protein blocks the trafficking of GABAR, a

principal GABA-gated ion channel that plays important roles in neural

transmission, to the surface of cells infected with BDV or transfected

with the P gene. We proposed that during BDV infection, P protein binds

to GABARAP, shifts the distribution of GABARAP from cytoplasm to

nucleus, and disrupts the trafficking of GABA receptors to the cell

membranes, which may result in the inhibition of GABA-induced currents

and in the enhancement of hyperactivity and anxiety.

PMID: 18815298