HIV-1 Vpr protein promotes neuronal deregulation: Mechanisms and Players Maryline Santerre1, Ying Wang1, Jeannie Chen2, Bassel E Sawaya1,3* 1Molecular Studies of Neurodegenerative Diseases Lab, FELS Institute, 3 Department of Neurology ; Lewis Katz School of Medicine - Temple University Philadelphia, PA 19140; USA; 2IMemory & Brain Research Center, Department of Neuroscience Baylor College of Medicine, Houston, Texas 77030, USA *Corresponding Author: Bassel E Sawaya, PhD, B.Eng, MS (IME), MBA
Disruption of Mitochondria Axonal transport (MAT), essential for the maintenance of synaptic and neuronal integrity and function, has been identified in neurodegenerative diseases. Whether HIV-1 viral proteins affect mitochondria axonal transport is unknown, albeit HIV-associated neurocognitive disorders occur in around half of the patients living with HIV. Therefore, we sought to examine the effect of HIV-1 viral protein R (Vpr) on mitochondria axonal transport.
We demonstrated that addition of recombinant Vpr protein reduced the ratio of moving mitochondria associated with (i) reduction of mitochondrial energy supply (less ATP), and (ii) loss of microtubule stability as demonstrated by inconsecutive distribution of acetylated a-tubulin along the axons.
These results indicated that HIV-1 Vpr protein disrupts the Mitochondria Axonal transport (MAT), essential for the maintenance of synaptic and neuronal integrity and function (a marker of neurodegenerative diseases). The effect of HIV-1 proteins on MAT disruption remains understudied. Searching for the mechanisms involved, we found that Vpr induces accumulation and aggregation of alpha Synuclein (aSyn) protein, which has been shown to affect mitochondrial energy and microtubules fragmentation leading to MAT impairments.
Accumulation of aSyn is normally associated with its aggregation, increased toxicity and alteration of neuronal communication leading to spatial memory loss and premature brain aging. Interestingly, Vpr lost its negative effect in the absence of in neurons which led us to conclude that the effect of Vpr is mediated through aSyn. Further, treatment of the cells with Rapamycin prevents aSyn aggregation and hence altered Vpr negative effect.
This is the FIRST report that demonstrates a role of aSyn along with the MAT in HAND development, also the first study to demonstrate that HIV-1 Vpr induces accumulation of aSyn in cells, in human tissue and in animal model. We suggest the use of RAPAMYCIN to prevent aSyn gain of functions and to establish a new therapeutic strategy to mitigate cognitive impairments associated with HIV-1 infection in HIV/AIDS patients. This work was supported by R01 grants awarded to BES from the National Institute of Health (NINDS, NIMH, NIA).
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