Parkinson's Disease: Biomarkers of Early Discovery
By: Mark Tingey, Katelyn Roberts, and Meredith Paterson
Parkinson’s disease is often referred to as a silent disease. It often begins in very innocuous ways, small ticks and behaviors that are almost imperceptible. This is how it began with Alan Alda. In a recent interview, he explained that he first suspected something was amiss when he had a dream. In this dream, he was panicked and convinced that he needed to defend himself. Upon waking, he realized he had been using a pillow as a weapon to fend off his wife. This somewhat humorous anecdote undercuts the seriousness of what this dream meant, this dream was an indication that Mr. Alda had a neurodegenerative disorder.
Delayed Diagnosis Means Delayed Treatment
As with many of the neurodegenerative diseases, there is no easy diagnostics methodology in place. Current diagnosis are made by a combination of brain scans and qualitative tests which measure behavior. Unfortunately, this requires the disease to progress to a sufficient stage for serious symptoms to be evident. This is what occurred with Mr. Alda. Years after he first began to suspect he may be ill, his thumb began to exhibit the characteristic pitch and roll movements of Parkinson’s Disease (PD). Shortly thereafter, Mr. Alda received a brain scan to confirm what the physical symptoms suggested. The brain scan confirmed the physicians suspicions, Mr. Alda had Parkinson’s Disease.
The Varied Manifestations of PD
Mr. Alda’s dream may seem somewhat incongruous when considered with what most people consider to be the symptoms of Parkinson’s Disease. The symptoms most commonly associated with PD are stiff muscles, poor balance, tremors, rhythmic (pitch and roll) muscle contractions. However, this list is far from complete. PD affects more than just motor function. It affects cognitive ability, mood, energy levels and even can result in a distorted or impaired sense of smell. The symptoms associated with Mr. Alda’s dream, specifically, flailing, kicking, and punching in self-defense are early indicators of Parkinson’s Disease. In the simplest terms, the majority of the rest you receive from sleep, comes from something called REM. When you are sufficiently relaxed, your body turns off all non-autonomic functions and enters REM sleep. During this time, no signals from your brain should be telling your body to move. However, an early indicator of Parkinson’s Disease is sudden and violent movements, often accompanied by feelings of fight or flight, during REM sleep. These disruptions indicate that erroneous signals are being sent inappropriately by the brain and is one of the earliest symptoms of Parkinson’s Disease.
The story of Mr. Alda is a very common one. Nearly one million people in the United States alone live with Parkinson’s Disease. Each one of these people, like Mr. Alda, could not be diagnosed until their disease progressed sufficiently to begin exhibiting serious symptoms. This is not due to negligence on the part of the physicians or the patients, rather due to an outmoded and inefficient diagnostic methodology. As no blood tests, urine tests, or other biochemical tests exist, it is the symptoms patients are experiencing that bring them to neurologists for help. Symptoms ranging from resting tremors, to changes in the pace of movement, to problems with their balance. Suddenly, Parkinson’s sufferers find that they are no longer able to accomplish simple tasks. Even simple things such as feeding ones self can eventually become an impossible task.
Biomarkers- The Future of Diagnostics
Parkinson’s Disease, like many degradative diseases, progresses as time goes on. There is currently no way to reverse damage done, but current treatments aim to slow degeneration and thereby improve quality of life. Therefore, early detection is key. Early detection means interventive treatment which may prevent the manifestation of PD symptoms entirely.
As has been noted in an earlier article, great strides are being made in finding effective biomarkers for Alzheimer’s. The concept of a biomarker is universal. A biomarker is simply a biological condition or structure which is present only when the patient is diseased. Finding an effective biomarker for neurodegenerative diseases is extremely complex, as many pathogenic proteins are only pathogenic when they are not degraded appropriately. This has led many scientists to shift their paradigm and begin looking not at base proteins, but the ubiquitylation patterns associated with specific pathogenic proteins.
Ubiquitin- A Promising Target for Parkinson's Research
In other neurodegenerative diseases, such as Alzheimer’s Disease and Parkinson’s Disease, the malfunction in the Ubiquitin Proteasome System (UPS) results in an overabundance of ubiquitylated proteins. In a healthy UPS, these proteins would be degraded by proteasomes shortly after becoming ubiquitylated. However, due to a failure in the UPS, these proteins are not degraded. Rather, overabundant proteins are pathogenic in nature, driving the symptoms or, in some cases, instigating the progression of the neurodegenerative disease.
In Parkinson’s Disease, the break-down of the UPS allows for a build up a protein called Alpha-Synuclein. This protein is particularly interesting to look at in PD for a number of reasons. First, the function of Alpha-Synuclein in healthy brains is unknown. Second, Alpha-Synuclein is the primary component of protein clumps called Lewy Bodies, one of the hallmark structures of neurodegenerative disease. Lewy Bodies are aggregates of proteins that develop inside of nerve cells and alter chemical interactions within and around the cell. These alterations lead to mood changes, memory problems, and motor difficulties. In some cases, Lewy Body aggregation strongly contributes to multi-system failure. Lewy Bodies themselves are a good indicator of neurodegenerative disease, but to be an effective biomarker it must be unique to a certain condition. Lewy Bodies are found in AD, PD, Dementia, and occasionally in un-diseased brains.
New Technologies Enable Novel Discoveries
The true challenge in identifying appropriate biomarkers is the relative scarcity of pathogenic proteins in patient samples. Mass spectrometry and other proteomic tools require a certain amount of protein to be able to accurately identify if the protein is present.LifeSensors' TUBEs technology enables researchers to enrich for ubiquitylated proteins. This capability enables scientists to pull significant amounts of ubiquitylated proteins from patient samples, thereby enabling them to identify the relative fractions of ubiquitylated proteins. Such a study would enable researchers to identify specific patterns of ubiquitylation which could serve as an accurate biomarker.
Therefore, scientists at LifeSensors, as well as our collaborators around the world, strongly believe that biomarkers for Parkinson’s Disease and other Neurodegenerative Diseases will be found byassaying the UPS. While research in this area is very much in the early stage, preliminary evidence strongly suggests that a series of ubiquitylated pathogenic proteins may form the basis of the world’s first, accurate, and proactive diagnostic assay.
The dream that Alan Alda had, told him that something may not be right with his body. He then had to wait for his body to irreparably degenerate to a degree where a diagnosis of Parkinson’s Disease could be given. We at LifeSensors have a dream as well. We envision a world where Mr. Alda’s story is never repeated; a world where blood tests for Parkinson’s Disease are as standard as having cholesterol checked; a world where an accurate diagnosis will occur before any symptoms appear, interventive treatments can begin, and the terrible fate suffered by millions around the world can be a thing of the past. We soon hope to help make this world a reality.
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