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Genetic Underpinnings of AMD, Other Diseases Revealed in YSPH Studies

January 29, 2015

A Yale School of Public Health researcher who discovered the gene behind age-related macular degeneration (AMD) has made new discoveries that increase the understanding of the mechanisms behind AMD and other diseases, including Parkinson’s disease.

Associate Professor Josephine Hoh, Victoria Patterson, associate research scientist in the Department of Environmental Health Science, and colleagues used a reverse genetic approach to reveal the underlying biology associated with disease conditions.

The first study, published in the journal PLOS ONE, explains the relationship between high temperature requirement serine protease A1 (HtrA1), and Protoporphyrin IX (PPP-IX), and provides a window into understanding how HtraA1 is implicated in human disease. A protein that has been associated with several diseases, HtrA1 is not well understood, but defects in it have been connected with increased risk of AMD, arthritis, the brain disease CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), metastasis of certain cancers, as well as a resistance to chemotherapy-induced toxicity.

Patterson, Hoh and their team looked for other proteins that may react with HtrA1 to alter its effects, and found a link with PPP-IX, indicating that further analysis of this interaction between the proteins may shed light into the pathogenesis of AMD, CARASIL and other diseases, as potentially spur the discoveries of effective therapies.

“We started with an unbiased screening in two human cancer cell lines as the first step to uncovered bioactive small molecules that interacted with HtrA1. This resulted in seven positive hits,” Patterson said. “This work is conceptually simple but the amount of efforts involved in detailed characterization followed by validation and then revalidation of each experimental step can not be overstated. In the long run, this study will have the profound impact and a direct application to the effective drug design for treatment and intervention.”

In a second paper, also published in PLOS ONE, Patterson, Hoh and colleagues examined HtrA2, a protein similar to HtrA1. HtrA2 is a mitochondrial protein. Polymorphisms in HtrA2 increased person’s chances in getting Parkinson’s disease. Armed with the knowledge that mice that lack this protein develop Parkinson’s-like symptoms, the team bred mice with a neuron-specific deletion of HtrA2. This resulted animals in poor growth, thymus and spleen atrophy, ataxia and early death. Since the knockout of HtrA2 in the neuron led to the same effect observed when there is a total deletion of the protein, Patterson, Hoh and their team were able to conclude that HtrA2 is most crucial for the proper development of neurons, although it is also essential for other cells in our body.

Further, the researchers detected increased cell death in the cerebellum of the affected mice, and to a lesser extent in the stratum, the part of the brain impacted in Parkinson’s. They also detected defective processing of OPA1, a key molecule for mitochondrial growth and maintenance. The results demonstrate for the first time the mitochondrial anomalies in the cerebellum with HtrA2 deficiency. With this knowledge, future studies may be better able to determine whether HtrA2 mutations lead to the cerebellar pathology in Parkinson’s disease patients, potentially leading to earlier diagnosis and better treatment of the disease.

In 2005 and 2006, Hoh led a group of Yale researchers in the two discoveries of the genes responsible for AMD, clearing a path to better treatment of a debilitating eye disease that leads to blindness in older people, and is predicted to affect 196 million people globally by 2020. The two recent studies will serve as a starting point to achieve Hoh’s goal of understanding the genetic risks of diseases that impact public health.

Submitted by Denise Meyer on January 30, 2015