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

July 3, 2017
A Parkinson's disease brain sample, stained with an antibody that only recognizes the N103 chunk of alpha-synuclein, which is generated through cleavage by AEP. Credit: From Zhang et al NSMB (2017).

Alzheimer's disease and Parkinson's disease are not the same. They affect different regions of the brain and have distinct genetic and environmental risk factors.

But at the biochemical level, these two neurodegenerative diseases start to look similar. That's how Emory scientists led by Keqiang Ye, PhD, landed on a potential drug target for Parkinson's.

In both Alzheimer's (AD) and Parkinson's (PD), a sticky protein forms toxic clumps in . In AD, the troublemaker 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 an enzyme (asparagine endopeptidase or AEP) that trims tau in a way that makes it more sticky and toxic. Drugs that inhibit AEP have beneficial effects in Alzheimer's animal models.

In a new Nature Structural and Molecular Biology paper, Emory researchers show that AEP acts in the same way toward .

"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."

A particular chunk of alpha-synuclein produced by AEP's scissors can be found in samples of brain tissue from patients with PD, but not in control samples, Ye's team found.

In control brain samples AEP was confined to lysosomes, parts of the cell with a garbage disposal function. But in PD samples, AEP was leaking out of the lysosomes to the rest of the cell.

The researchers also observed that the chunk of alpha-synuclein generated by AEP is more likely to aggregate into clumps than the full length protein, and is more toxic when introduced into cells or mouse brains. In addition, alpha-synuclein mutated so that AEP can't cut it is less toxic.

Ye cautions that AEP is not the only enzyme that cuts alpha-synuclein into various toxic pieces, and the full-length alpha-synuclein protein is still able to aggregate and cause harm. Nevertheless, he says his team is moving on to testing drugs that inhibit AEP in Parkinson's animal models.

Explore further: Pre-clinical study suggests Parkinson's could start in gut endocrine cells

More information: Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson's disease, Nature Structural and Molecular Biology, DOI: 10.1038/nsmb.3433

Related Stories

Pre-clinical study suggests Parkinson's could start in gut endocrine cells

June 15, 2017
Recent research on Parkinson's disease has focused on the gut-brain connection, examining patients' gut bacteria, and even how severing the vagus nerve connecting the stomach and brain might protect some people from the debilitating ...

Parkinson's is partly an autoimmune disease, study finds

June 21, 2017
Researchers have found the first direct evidence that autoimmunity—in which the immune system attacks the body's own tissues—plays a role in Parkinson's disease, the neurodegenerative movement disorder. The findings raise ...

A human enzyme can reduce neurotoxic amyloids in a mouse model of dementia

June 27, 2017
A naturally occurring human enzyme -called cyclophilin 40 or CyP40- can unravel protein aggregates that contribute to both Alzheimer's disease and Parkinson's disease, according to a study publishing June 27 in the open access ...

Balance and movement improved in animal model of Parkinson's disease

June 12, 2017
Researchers at UCLA have developed a molecular compound that improves balance and coordination in mice with early stage Parkinson's disease. Further, the drug, called CLR01, reduced the amount of a toxic protein in the brain ...

CRISPR tech leads to new screening tool for Parkinson's disease

June 5, 2017
A team of researchers at the University of Central Florida is using breakthrough gene-editing technology to develop a new screening tool for Parkinson's disease, a debilitating degenerative disorder of the nervous system. ...

Research provides new understanding of Parkinson's and Alzheimer's disease and opens path to treatment

October 26, 2016
A team of scientists at Baylor College of Medicine and Texas Children's Hospital has discovered that in three separate laboratory models, the protein TRIM28 can promote the accumulation of two key proteins that drive the ...

Recommended for you

New research suggests high-intensity exercise boosts memory

November 22, 2017
The health advantages of high-intensity exercise are widely known but new research from McMaster University points to another major benefit: better memory.

To forget or to remember? Memory depends on subtle brain signals, scientists find

November 22, 2017
The fragrance of hot pumpkin pie can bring back pleasant memories of holidays past, while the scent of an antiseptic hospital room may cause a shudder. The power of odors to activate memories both pleasing and aversive exists ...

Pitch imperfect? How the brain decodes pitch may improve cochlear implants

November 22, 2017
Picture yourself with a friend in a crowded restaurant. The din of other diners, the clattering of dishes, the muffled notes of background music, the voice of your friend, not to mention your own – all compete for your ...

What if consciousness is not what drives the human mind?

November 22, 2017
Everyone knows what it feels like to have consciousness: it's that self-evident sense of personal awareness, which gives us a feeling of ownership and control over the thoughts, emotions and experiences that we have every ...

Now you like it, now you don't: Brain stimulation can change how much we enjoy and value music

November 20, 2017
Enjoyment of music is considered a subjective experience; what one person finds gratifying, another may find irritating. Music theorists have long emphasized that although musical taste is relative, our enjoyment of music, ...

MRI uncovers brain abnormalities in people with depression and anxiety

November 20, 2017
Researchers using MRI have discovered a common pattern of structural abnormalities in the brains of people with depression and social anxiety, according to a study presented being next week at the annual meeting of the Radiological ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.