Genetic Variants' Role in Increasing Parkinson's Disease Risk Investigated

Boston University School of Medicine (BUSM) investigators have led the first genome-wide evaluation of genetic variants associated with Parkinson's disease (PD). The study, which is published online in PLOS ONE, points to the involvement of specific genes and alterations in their expression as influencing the risk for developing PD.

Jeanne Latourelle, DSc, assistant professor of neurology at BUSM, served as the study's lead author and Richard H. Myers, PhD, professor of neurology at BUSM, served as the study's principal investigator and senior author.

A recent paper by the PD Genome Wide Association Study Consortium (PDGC) confirmed that an increased risk for PD was seen in individuals with genetic variants in or near the genes SNCA, MAPT, GAK/DGKQ, HLA and RIT2, but the mechanism behind the increased risk was not determined.

"One possible effect of the variants would be to change the manner in which a gene is expressed in the brains, leading to increased risk of PD," said Latourelle.

To investigate the theory, the researchers examined the relationship between PD-associated genetic variants and levels of gene expression in brain samples from the frontal cortex of 26 samples with known PD and 24 neurologically healthy control samples. Gene expression was determined using a microarray that screened effects of genetic variants on the expression of genes located very close to the variant, called cis-effects, and genes that are far from the variant, such as those on a completely different chromosome, called trans-effects.

An analysis of the cis-effects showed that several genetic variants in the MAPT region showed a significant association to the expression of multiple nearby genes, including gene LOC644246, the duplicated genes LRRC37A and LRRC37A2 and the gene DCAKD. Significant cis-effects were also observed between variants in the HLA region on chromosome 6 and two nearby genes HLA-DQA1 and HLA-DQA1. An examination of trans-effects revealed 23 DNA sequence variations that reached statistical significance involving variants from the SNCA, MAPT and RIT2 genes.

"The identification of the specific altered genes in PD opens opportunities to further study them in model organisms or cell lines with the goal of identifying drugs which may rectify the defects as treatment for PD," said Myers.

Journal Reference:

1. Jeanne C. Latourelle, Alexandra Dumitriu, Tiffany C. Hadzi, Thomas G. Beach, Richard H. Myers. Evaluation of Parkinson Disease Risk Variants as Expression-QTLs. PLoS ONE, 2012; 7 (10): e46199 DOI: 10.1371/journal.pone.0046199

Courtesy: ScienceDaily

HIV Drug Shows Efficacy in Treating Mouse Models of HER2+ Breast Cancer, Study Suggests

The HIV protease inhibitor, Nelfinavir, can be used to treat HER2-positive breast cancer in the same capacity and dosage regimen that it is used to treat HIV, according to a study published October 5 in the Journal of the National Cancer Institute.

Breast cancer is one of the most common causes of cancer deaths in the U.S. with approximately 39,520 women succumbing to the disease in 2011. HER2-postive breast cancer is known to be more aggressive and less responsive to treatments compared to other types of breast cancer. Nelfinavir has been shown to inhibit the growth of some types of cancers and has been used in clinical trials as either a chemotherapeutic agent or a radiosensitizer for cancer therapy. However, its effect on HER2-positive breast cancer is unknown.

In order to determine the effects of Nelfinavir on HER2-positive breast cancer, Joong Sup Shim, Ph.D., of the Department of Pharmacology and Molecular Sciences at Johns Hopkins School of Medicine and colleagues screened the Johns Hopkins Drug Library and identified a number of inhibitors of breast cancer cells, a subset of which was then used to pharmacologically profile seven genotypically individual breast cancer cell lines. After identifying Nelfinavir as a selective inhibitor of HER2-positive cells, the researchers determined the antitumor activity of the inhibitor in mouse models of human breast cancer.

The researchers found that Nelfinavir inhibited the growth of HER2-positive tumors in mice. They also found that the concentrations of Nelfinavir needed to inhibit HER2-positive cancer cells in vitro are consistent with dosage regimens used for HIV patients. "With a relatively low toxicity profile and much available information on its drug-drug interactions and on pharmacokinetics, Nelfinavir is ready for clinical testing in HER2 breast cancer patients," the authors write, adding that this discovery has, "important implications in the development of Nelfinavir and its analogs as new anticancer agents."

Journal Reference:

1. Joong Sup Shim, Rajini Rao, Kristin Beebe, Len Neckers, Inkyu Han, Rita Nahta, and Jun O. Liu. Selective Inhibition of HER2-Positive Breast Cancer Cells by the HIV Protease Inhibitor Nelfinavir. J Natl Cancer Inst, October 5, 2012 DOI: 10.1093/jnci/djs396

Courtesy: ScienceDaily