RT Journal Article
SR Electronic
T1 SIV-mediated synaptic dysfunction is associated with an increase in synapsin site 1 phosphorylation and impaired PP2A activity
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 0178-19
DO 10.1523/JNEUROSCI.0178-19.2019
A1 Masoud Shekarabi
A1 Jake A. Robinson
A1 Mandy D. Smith
A1 Tricia H. Burdo
YR 2019
UL http://www.jneurosci.org/content/early/2019/07/03/JNEUROSCI.0178-19.2019.abstract
AB Although the reduction of viral loads in people with HIV (PWH) undergoing combination antiretroviral therapy (cART) has mitigated AIDS related symptoms, the prevalence of neurological impairments has remained unchanged. HIV-associated CNS dysfunction includes impairments in memory, attention, memory processing and retrieval. Here, we show a significant site-specific increase in the phosphorylation of Syn I serine 9, site 1, in the frontal cortex lysates and synaptosome preparations of male rhesus macaques infected with simian immunodeficiency virus (SIV) but not in uninfected or SIV-infected ART animals. Furthermore, we found that a lower protein phosphatase 2A (PP2A) activity, a phosphatase responsible for Syn I (S9) dephosphorylation, is primarily associated with the higher S9 phosphorylation in the frontal cortex of SIV-infected macaques. Comparison of brain sections confirmed higher Syn I (S9) in the frontal cortex and greater coexpression of Syn I and PP2A A subunit which was observed as perinuclear aggregates in the somata of the frontal cortex of SIV-infected macaques. Synaptosomes from SIV-infected animals were physiologically tested using a synaptic vesicle endocytosis assay and FM™4-64 dye showing a significantly higher baseline depolarization levels in synaptosomes of SIV+ infected than uninfected control or ART animals. A PP2A-activating FDA approved drug, FTY720, decreased the higher synaptosome depolarization in SIV-infected animals. Our results suggest an impaired distribution and lower activity of serine/threonine phosphatases in the context of HIV infection may cause an indirect effect on the phosphorylation levels of essential proteins involving in synaptic transmission supporting the occurrence of specific impairments in the synaptic activity during SIV infection.SIGNIFICANCE STATEMENTEven with antiretroviral therapy (ART), neurocognitive deficits, including impairments in attention, memory processing and retrieval, are still major concerns in people living with HIV. Here, we utilized the rhesus macaque SIV model with and without ART to study the dynamics of phosphorylation of key amino acid residues of synapsin I (Syn I), which critically impacts synaptic vesicle (SV) function. We found a significant increase in Syn I phosphorylation at serine 9, which was driven by dysfunction of serine/threonine protein phosphatase 2A in the nerve terminals. Our results suggest an impaired distribution and lower activity of serine/threonine phosphatases in the context of HIV infection may cause an indirect effect on the phosphorylation levels of essential proteins involving in synaptic transmission.