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Borna disease virus blocks potentiation of presynaptic activity through inhibition of protein kinase C signaling.

ABSTRACT: Infection by Borna disease virus (BDV) enables the study of the molecular mechanisms whereby a virus can persist in the central nervous system and lead to altered brain function in the absence of overt cytolysis and inflammation. This neurotropic virus infects a wide variety of vertebrates and causes behavioral diseases. The basis of BDV-induced behavioral impairment remains largely unknown. Here, we investigated whether BDV infection of neurons affected synaptic activity, by studying the rate of synaptic vesicle (SV) recycling, a good indicator of synaptic activity. Vesicular cycling was visualized in cultured hippocampal neurons synapses, using an assay based on the uptake of an antibody directed against the luminal domain of synaptotagmin I. BDV infection did not affect elementary presynaptic functioning, such as spontaneous or depolarization-induced vesicular cycling. In contrast, infection of neurons with BDV specifically blocked the enhancement of SV recycling that is observed in response to stimuli-induced synaptic potentiation, suggesting defects in long-term potentiation. Studies of signaling pathways involved in synaptic potentiation revealed that this blockade was due to a reduction of the phosphorylation by protein kinase C (PKC) of proteins that regulate SV recycling, such as myristoylated alanine-rich C kinase substrate (MARCKS) and Munc18-1/nSec1. Moreover, BDV interference with PKC-dependent phosphorylation was identified downstream of PKC activation. We also provide evidence suggesting that the BDV phosphoprotein interferes with PKC-dependent phosphorylation. Altogether, our results reveal a new mechanism by which a virus can cause synaptic dysfunction and contribute to neurobehavioral disorders.

SUBMITTER: Volmer R

PROVIDER: S-EPMC1401496 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson's Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and α-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of α-synuclein, and enhances formation of pathologic α-synuclein, particularly when synaptic activity is increased. α-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence α-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences α-synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of α-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of α-synuclein. Live imaging of axonal transport of α-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on α-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases α-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of α-synuclein-GFP. In vivo, LRRK2 inhibition increases α-synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of α-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of α-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.

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Borna disease virus blocks potentiation of presynaptic activity through inhibition of protein kinase C signaling.

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