We propose to investigate the relationship between the inherited genotype of catechol-o-methyl transferase (COMT) and the protection against the development of HIV related impaired executive function, which is lost when methamphetamine (METH) is used by the affected individuals. We intend to focus on a common functional polymorphism, a Valine (Val) to Methionine (Met) substitution in exon 4 of the gene that alters the amino acid codon at position 108 (Val108Met) in the soluble-COMT (S-COMT) which is found in blood or position 158 (Val158Met) in the membrane-bound COMT (MB-COMT) located in the brain. This polymorphism results in a significant change in the enzymatic activity to degrade dopamine when the Val allele is not present. We have performed genotyping for the Val/Met alleles of the COMT gene in 270 subjects that include healthy controls;HIV infected/METH negative;METH positive/HIV uninfected;and HIV infected/METH positive individuals. We noted significantly lower levels of impairment in the healthy controls carrying a met allele and this allele continued to confer better executive functioning even in the HIV infected subjects. However, impairment of executive functioning was higher in the METH dependent and HIV infected/METH dependent groups regardless of COMT genotype with the protective effects of the met allele having been lost. The second finding is that in HIV infected individuals over 55 years that is a significant increase in the frequency of 1- synuclein deposition compared to controls. Our overarching hypothesis is that individuals with COMT-met allele conferred protection against HIV mediated frontal cognitive dysfunction, which is lost in the context of METH. We intend to assess the relationship between the inherited COMT genotype and documented meth use and executive function in life with neuropathological markers of neurodegeneration and inflammation in human brain tissue and in vitro human brain tissue cultures. Specifically we will assess the accumulation oxidative proteins, nitrotyrosine, lipid peroxidation, oxidative DNA damage and 1-synuclein deposition as these are associated with meth use and we have recently demonstrated a significant increase in 1-synuclein deposition in HIV infected individuals. We will further assess the molecular effects of methamphetamine to elucidate the process by which methamphetamine abrogates the protective effect of met/met COMT with the presumption that it may be related to oxidative stress. Such an understanding will in a future application facilitate the development of targeted therapies to prevent the methamphetamine related molecular dysfunction.
Methamphetamine users are the fastest growing population in the United States to acquire HIV infection. Furthermore, HIV infected methamphetamine users suffer the most severe cognitive impairment. In this investigation we are proposing to investigate the relationship between the inherited variant of the catechol-o-methyl-transferase (COMT) gene and HIV associated neurocognitive disorder (HAND) in methamphetamine users.
| Lee, Ting Ting; Chana, Gursharan; Gorry, Paul R et al. (2015) Inhibition of catechol-O-methyl transferase (COMT) by tolcapone restores reductions in microtubule-associated protein 2 (MAP2) and synaptophysin (SYP) following exposure of neuronal cells to neurotropic HIV. J Neurovirol 21:535-43 |
