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Drug discovery: Alzheimer's, Parkinson's spurred by same enzyme

Though equally devastating, Alzheimer’s disease (AD) and Parkinson’s disease (PD) are very different disorders. They affect different regions of the brain and have distinctive genetic and environmental risk factors.

But at the biochemical level, these two neurodegenerative diseases start to look similar, spurred by the same enzyme. That’s how Emory scientists, led by Keqiang Ye, landed on a potential drug target for PD.

In both AD and PD, a sticky and potentially toxic protein forms clumps in brain cells. In AD, the substance inside cells is called tau, making up neurofibrillary tangles. In PD, the sticky protein is alpha-synuclein, forming Lewy bodies.

Ye and his colleagues had previously identified asparagine endopeptidase (AEP ), which trims tau in a way that makes it both more sticky and toxic. And they also discovered that drugs that inhibit AEP have beneficial effects in AD animal models.

In a paper released last year, Emory researchers revealed that AEP acts in the same way toward alpha-synuclein as it does toward tau. “In Parkinson’s, alpha-synuclein behaves much like tau in Alzheimer’s,” Ye says. “We reasoned that if AEP cuts tau, it’s very likely that it will cut alpha-synuclein, too.”

Even though Ye cautions that AEP is not the only enzyme that cuts alpha-synuclein into toxic pieces, and that full-length alpha-synuclein protein is still able to aggregate and cause harm, his team is moving to test drugs that inhibit AEP in PD animal models.

With contributions from the laboratories at Emory and in China — and support from the Michael J. Fox Foundation, the National Eye Institute, and the National Natural Science Foundation of China — it’s the kind of collaborative, breakthrough research that is a cornerstone of Emory’s reputation for innovation and excellence.

Protein foldings, new findings

AD, and other neurodegenerative conditions involving the abnormal folding of proteins, may also help kick-start chemical evolution and explain the emergence of life.

That’s a connection demonstrated in two papers by researchers at Emory and Georgia Institute of Technology.

“In the first paper, we showed that you can create tension between a chemical and physical system to give rise to more complex systems. And in the second paper, we showed that these complex systems can have remarkable and unexpected functions,” says David Lynn,

Asa Griggs Candler Professor of Chemistry and Biology, who led the research.

Researchers explored ways potentially to control and direct the processes of such proteins — known as prions, which drive several diseases of aging. The findings add to knowledge that might one day help prevent such diseases.

In other research developments, Emory investigators also identified a new target for Parkinson’s Disease — the discovery of a novel link between a protein called SV2C and the disease.

Prior research suggested the SV2C gene was associated with the curious ability of cigarette smoking to reduce PD risk. SV2C is part of a family of proteins involved in regulating the release of neurotransmitters in the brain. Dopamine depletion is a known feature of PD, and research shows SV2C controls the release of dopamine in the brain.

“Our research reveals a connection between SV2C and dopamine and suggests that drug therapies aimed at SV2C may be beneficial in PD or other dopamine-related disorders,” says Gary W. Miller, professor and associate dean for research at the Rollins School of Public Health and senior author of the study. 

Emory researchers also offered new insight into how a regulatory gene called LSD1 could be a central player in neurodegenerative diseases and a promising drug target. 

Removal of the LSD1 protein in adult mice induced changes in gene activity that look unexpectedly like AD, and researchers also found that the protein is perturbed in brain samples of humans with AD and frontotemporal dementia.

The discoveries were led by the lab of David Katz, assistant professor of cell biology at Emory School of Medicine, in collaboration with Allan Levey, director of Emory’s Alzheimer’s Disease Research Center.

Helping caregivers cope 

Emory researchers are also looking at neurodegenerative diseases beyond strictly scientific dimensions, examining how families, patients, and caregivers cope with AD.

Knowing that, for millions of Americans, the disease presents tough choices, Mi-Kyung Song, director of the Center for Nursing Excellence in Palliative Care at the Nell Hodgson Woodruff School of Nursing, is working to make decisions easier with regard to end-of-life care for people with AD. 

With a $3 million grant from the National Institute on Aging, Song will modify Sharing Patient’s Illness Representation to Increase Trust — an advance care plan she’s developed and tested — to help promote open, honest discussions among all those affected by the disease when dementia progresses to an advanced stage. 

Among other patient support efforts, the Emory Alzheimer’s Disease Research Center received a $50,000 grant from the Alzheimer’s Foundation of America for education, screening, and community outreach efforts geared at African Americans in metro Atlanta, who are more than twice as likely to develop AD compared to European Americans.

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