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Wang Y , Santerre M , Tempera I , Martin K , Mukerjee R , Sawaya BE
HIV-1 Vpr disrupts mitochondria axonal transport and accelerates neuronal aging
Neuropharmacology. 2017 May 1;117 :364-375
PMID: 28212984    PMCID: PMC5397298   
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Abstract
Disruption of mitochondria axonal transport, 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. Using mice primary neuronal cultures, we demonstrated that 4-day Vpr treatment reduced the ratio of moving mitochondria associated with (i) less energy (ATP) supply, (ii) reduction in Miro-1 and (iii) increase of alpha-synuclein which led to loss of microtubule stability as demonstrated by inconsecutive distribution of acetylated alpha-tubulin along the axons. Interestingly, the effect of Vpr on mitochondria axonal transport was partially restored in the presence of bongkrekic acid, a compound that negatively affected the Vpr-adenine nucleotide translocator (ANT) interaction and totally restored the ATP level in neurons. This indicated Vpr impaired mitochondria axonal transport partially related to its interaction with ANT. The above effect of Vpr was similar to the data obtained from hippocampal tissues isolated from 18-month-old aging mice compared to 5-month-old mice. In accord with previous clinical findings that HIV infection prematurely ages the brain and increases the susceptibility to HAND, we found that Vpr induced aging markers in neurons. Thus, we concluded that instead of causing cell death, low concentration of HIV-1 Vpr altered neuronal function related with inhibition of mitochondria axonal transport which might contribute to the accelerated neuronal aging.
Notes
1873-7064 Wang, Ying Santerre, Maryline Tempera, Italo Martin, Kayla Mukerjee, Ruma Sawaya, Bassel E R01 MH093331/MH/NIMH NIH HHS/United States R01 NS076402/NS/NINDS NIH HHS/United States T32 NS076401/NS/NINDS NIH HHS/United States R01 NS059327/NS/NINDS NIH HHS/United States R01 NS040673/NS/NINDS NIH HHS/United States Journal Article England Neuropharmacology. 2017 May 1;117:364-375. doi: 10.1016/j.neuropharm.2017.02.008. Epub 2017 Feb 14.