Breaking Barriers: SHLP2 and Parkinson's Progress

Pop. Spark. Flick. That’s the sound of your brain functioning, processing electrochemical signals from neuron to neuron during your fourth period math class. You are simultaneously writing notes and listening to the teacher, all while scrambling to finish your other homework due next period. This is possible because your brain processes information in parallel, meaning that the coordinated activity of billions of neurons inside your brain allows it to handle multiple tasks in one setting. Those suffering from late stage Parkinson’s disease would not be able to handle this level of multitasking; in fact, they wouldn’t even be able to complete simple tasks such as movement.

Parkinson’s disease causes deterioration in cognitive movement where patients show symptoms such as tremors, loss of balance and coordination, and stiffness. While the root cause of Parkinson’s is unknown, many scientists continue to test theories of it being related to environmental triggers, genetics, and aging. However, all symptoms related to Parkinson’s can be traced back to the degradation of neurons that produce neurotransmitters that are necessary for the body’s movement and coordination. Along with this decline of neurotransmitter production, Parkinson’s can worsen due to neuroinflammation, which is the inflammatory response that initiates a cascade of damaging processes within the brain. In response to triggers in the brain formed after the loss of neurotransmitter producing neurons such as oxidative stress and misfolded proteins, pro-inflammatory molecules like cytokines and chemokines become released which puts the brain into a chronic inflammatory state. This state is harmful because it can directly damage neurons and disrupt the brain’s environment, which worsens Parkinson’s. 

As the disease progresses, symptoms may worsen and eventually may lead to more alarming mental/physical issues such as sleep deprivation, loss of memory, fatigue, and depression. These symptoms can account for why people with Parkinson’s cannot multitask or even carry out simple tasks without struggling. This deterioration in movement can be accounted for by apoptosis (cell death) and impairment within cells of basal ganglia, the part of the brain that affects movement, that occurs when one is diagnosed with Parkinson’s. Since these cells are responsible for the production of dopamine, as these nerve cells die, their ability to produce dopamine slows as well, which in turn causes the symptoms we often see in Parkinson’s disease (in movement especially). This is because dopamine serves as a chemical messenger, or a neurotransmitter, that sends signals from the substantia nigra (part of the brain that controls movement/vision) to the corpus striatum (part of the brain responsible for motor control/decision making) to allow for movement within the body.

Dopamine is only one of many neurotransmitters that Parkinsons affects. Those diagnosed lose nerve endings that are in charge of producing norepinephrine, which is a neurotransmitter of the sympathetic nervous system that controls imperative functions of the body, such as heart rate and blood pressure. The loss of these nerve endings relates to the bigger phenomenon occurring here of neurotransmitter depletion, where multiple neurotransmitter systems (like dopamine) are being impacted. Lower norepinephrine movement would explain the effects that are not related to movement such as fatigue, decreased blood pressure, and slowed movement of food through the digestive tract. In addition to the decreased production of these neurotransmitters, Parkinson’s symptoms can intensify and spread throughout the brain due to the building of ‘Lewy bodies’, which are clumps of the protein alpha-synuclein, which can become toxic and eventually damage brain cells. Alpha‐synuclein​​ interacts with DNA to trigger marked nuclear degradation, or more ‘pronounced’ levels of breakdown in the nucleus of, in this case, nerve cells. Since the nucleus is a critical organelle responsible for metabolic processes such as cellular respiration that is necessary for survival, these clumps can quickly contribute to apoptosis of these cells. Since these clumps can get passed from one neuron to another, this nuclear degradation can quickly spread throughout the brain. This results in worsened effects such as prolonged dementia, especially when spread to important neurotransmitters such as acetylcholine, which is responsible for processing information and memory. 

However, Parkinson’s disease is often inherited and most people that are diagnosed develop the condition in their older days, usually when they reach their 60s. There is no current cure for Parkinson’s, but supportive therapies and short-term relief medication are available to control symptoms. Yet, a newly found genetic mutation gives hope for treatments not only in just Parkinson’s disease, but also therapies involving illnesses such as diabetes, strokes, and heart attacks. 

In a study done by Pinchas Cohen, Su-Jeong Kim, and other supporting researchers from the USC Leonard Davis School of Gerontology, a variant of SHLP2, which contains a change in one letter of the protein’s genetic code, was found as a mitochondrial microprotein. From a series of experiments that involved a lab-developed microprotein pipeline and thousands of human study subjects that also took part in heart studies, researchers were able to show that people that carried this variant are half as likely to develop Parkinson’s as those who do not carry it. This research team used targeted mass spectrometry, a method that analyzes predefined ions within a sample, providing precise identification of specific molecules to find the peptide’s (chains of amino acids that eventually build up to proteins) presence in neurons and found that this variant binds to mitochondrial complex 1, an enzyme in the mitochondria. This enzyme has been studied and its decline in activity has been linked to many diseases such as strokes, heart attacks, and Parkinson’s. For instance, the decline in mitochondrial enzyme-I activity during strokes causes an imbalance between forward electron transport and reverse electron transport  (both processes responsible for the direction of electrons through the mitochondria), leading to oxidative stress and neuron death which can contribute to the severity of strokes. However, overall, this variant of SHLP2 in this form is rare and is primarily found in people of European descent. While the study does not specify why this variant is mostly found in European ancestry, it was noted that it is still unlikely to be found within most people since the variant was only found in one percent of Europeans. 

In a previous study, Cohen originally found that SHLP2 production rose in order for the body to counteract the path of Parkinson’s disease incoming into the body. In addition, the same study showed that the SHLP2 variant was found to have more stability than its typical type and is linked to protection against mitochondrial dysfunction. This is especially crucial to note since mitochondrial dysfunction is linked to multiple harmful diseases, as we saw with strokes and Parkinson’s. Therefore, targeting this pathway of the mitochondria may broaden the scope of new therapies and improve outcomes for Parkinson’s disease patients. 

Su-Jeong Kim, a assistant professor of gerontology that took part in the experiment, explains that these benefits of SHLP2 have not only been groundbreaking for research involving Parkinson’s, but it also has given new insights into the process of finding new treatments for others. “These findings may guide the development of therapies and provide a roadmap for understanding other mutations found in mitochondrial microproteins,” Kim said. The discovery of SHLP2 and its variant’s ability to protect against mitochondrial dysfunction and oxidative stress highlights that this gives new insights to treatment methods not only in Parkinson’s, but in other neurological diseases as well. By understanding the importance of variants in mitochondrial health in these diseases, researchers can use this to provide a promising direction for these diseases using targeted treatments. This opens up the world to examine proteins in the mitochondria as a new way to find possible cures for diseases.