PREP-ing to treat Parkinson’s disease: A possible new direction in treatment of Parkinson’s

 

How prolyl oligopeptidase (PREP) may be working.

Yes, I know. The obvious first question is: What is prolil oligoopep..tid… whatever?

It’s really very simple. Prolyl oligopeptidase is a serine protease, that cleaves short peptides containing proline-residue.

All clear? Just kidding – I don’t even know what any of that means!

Prolyl oligopeptidase (or PREP) is an enzyme that is involved in the making and destruction of certain types of hormones and neuropeptides (Neuropeptides are a group of small molecules used by brain cells to communicate with each other). PREP is required for cutting certain bonds on some of these small molecules, allowing them to function normally or be broken down and recycled.

PREP can be found in cells from most of species – from bacteria to human – suggesting that it has important functions across evolution. In addition, PREP has been associated with amnesia, depression and blood pressure control.

What has PREP got to do with Parkinson’s disease?

Interestingly, PREP activity changes during the aging process. It also changes during neurodegenerative conditions, such as Alzheimer’s and Parkinson’s diseases. Given this situation, several PREP inhibitors were developed during the 1990s, and they were found to have a positive effect on memory and learning in animal models of Alzheimer’s disease

So what is known about PREP in Parkinson’s disease?

Back in 1987, a group of researchers noticed something interesting in the cerebrospinal fluid (the liquid surrounding the brain) of people with Parkinson’s disease. When the researchers compared normal healthy subjects with people who have Parkinson’s disease, they found that people with Parkinson’s disease exhibited a marked decrease in the activity of PREP in the cerebrospinal fluid. Interestingly, this decrease was not evident in the blood, suggesting that something was happening in the brain.

This observation was later followed up by other findings, where PREP was actually located in the postmortem brain. In people with Parkinson’s disease, they found that a very strong presence of PREP in the substantia nigra (the region which loses dopamine neurons in this condition). Interestingly, they also noted that PREP was co-localized with the Parkinson’s associated protein alpha synuclein (meaning where they found PREP, they also saw alpha synuclein). It is also interesting to note that they did not see this pattern in the brains of normal healthy controls or people with Alzheimer’s disease.

In 2008, another group found that PREP not only co-localized with alpha synuclein, but it was also doing something quite unexpected. When they put the proteins together in cell cultur, it showed an acceleration in the accumulation (or aggregation) of alpha synuclein. Aggregation of alpha synuclein is a key feature of the Parkinsonian brain. It is believed to be responsible for the presence of Lewy bodies (the dense circular clusters in cells in the brains of people with Parkinson’s disease) and may be involved in the cell death associated with the condition.

With the discovery that PREP is involved with the aggregation of alpha synuclein, the researchers suddenly had a new disease-related target to investigate further. Previously it was shown that PREP inhibitors can reduce the levels of alpha synuclein in a genetically engineered mouse that produces very high levels of alpha synuclein. They genetically engineered Parkinson’s disease in mice using viruses that cause the production of high levels of alpha synuclein in the dopamine neurons. This over-production of alpha synuclein causes problems for the dopamine neurons and some of those cells die off, in effect modeling what is happening in the brains of people with Parkinson’s disease.

Using a PREP inhibitor (KYP-2047, which is crosses the blood–brain barrier), the researchers were able to rescue the behavioral impairment caused by the viral over-production of alpha synuclein. In addition, the administration of the PREP inhibitor reduced the levels of certain types of alpha synuclein in the brain. The researchers also saw a mild neuroprotective effect with less dopamine neurons dying (perhaps if the study had continued for longer they might have seen a larger difference) and less dopamine dysfunction in the animals that received the PREP inhibitor, suggesting that treatment with the PREP inhibitor protected the dopamine neurons and restored their normal functions. The critical aspect of this study was that the PREP inhibitor treatment was only given to the animals after the behavioral/physical problems started, and it was still able to provide positive benefits to them. The researchers concluded that these results suggest that PREP inhibitors should be further investigated for Parkinson’s disease.

What does it all mean?

We desperately need some new and novel targets to help attack this disease, and PREP inhibitors represent a completely new approach. Yes, they are going after alpha synuclein (and the jury is still out as to whether alpha synuclein is a causal agent in the disease), but they are certainly taking a different route. While the alpha synuclein vaccines and antibodies currently being tested in clinic trials are removing free floating alpha synuclein, PREP inhibitors are stopping alpha synclein from actually aggregating. This is exactly the kind of new approach we are looking for. Whether PREP inhibitors reducing alpha synuclein aggregation is functionally a good thing for Parkinson’s disease requires further testing. For example, if alpha synuclein is playing an antimicrobial function by aggregating around bacteria/viruses, inhibiting that aggregation might not be a good thing – it might leave us more vulnerable to illness. But the good news here is that PREP inhibitors represent a new direction for us to explore in the treatment of Parkinson’s disease, and if blocking alpha synuclein aggregation does slow/halt the disease then PREP will definitely be worthy of further investigation.

Resources:

Title: Post-proline cleaving enzyme in human cerebrospinal fluid from control patients and parkinsonian patients.
Authors: Hagihara M, Nagatsu T.
Journal: Biochem Med Metab Biol. 1987 Dec;38(3):387-91.
PMID: 3481269

Title: Prolyl oligopeptidase colocalizes with α-synuclein, β-amyloid, tau protein and astroglia in the post-mortem brain samples with Parkinson’s and Alzheimer’s diseases.
Authors: Hannula MJ, Myöhänen TT, Tenorio-Laranga J, Männistö PT, Garcia-Horsman JA.
Journal: Neuroscience. 2013 Jul 9;242:140-50.
PMID: 23562579

Title: Prolyl oligopeptidase stimulates the aggregation of alpha-synuclein.
Authors: Brandt I, Gérard M, Sergeant K, Devreese B, Baekelandt V, Augustyns K, Scharpé S, Engelborghs Y, Lambeir AM.
Journal: Peptides. 2008 Sep;29(9):1472-8.
PMID: 18571285

Title: Inhibition of Prolyl Oligopeptidase Restores Spontaneous Motor Behavior in the α-Synuclein Virus Vector-Based Parkinson’s Disease Mouse Model by Decreasing α-Synuclein Oligomeric Species in Mouse Brain.
Authors: Svarcbahs R, Julku UH, Myöhänen TT.
Journal: J Neurosci. 2016 Dec 7;36(49):12485-12497.
PMID: 27927963

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