By Alison Hildebrandt

Referred to as the “Mother Board” by many physicians and scientists, the brain is responsible for much of how our body functions day-to-day. In particular, the autonomic nervous system regulates involuntary body functions such as heart rate, blood pressure, and body temperature. The cerebellum also plays a key role in the body’s coordination and ability to balance. Being that these systems play important roles in the functionality of the body from day-to-day, a flaw in these centers causes major disruptions. Neurodegenerative diseases are categorized by the effects that they have on our bodies. One disease of interest is Multiple System Atrophy (MSA), a fatal disease causing loss in motor function, abnormal heart rate, increased blood pressure, and body tremors [1].

The cause of these symptoms has been found to be the presence of prions within the brain [2]. Prions are proteins that are able to fold into multiple forms, which can cause negative effects that lead to diseases. In the development of MSA, the presence of an abnormally folded alpha-synuclein human protein has been found to be the cause of disruption within the autonomic nervous system [3].

MSA has shown symptoms similar to a more commonly known neurodegenerative disease: Parkinson’s disease. However, the key difference between the two diseases is the location of the prions found in the body [2]. Individuals suffering from MSA have been found to have abnormal alpha-synuclein proteins in oligodendrocytes [2]. These proteins then spread to the neurons, leading to poor development of myelin and thus poorly insulated neurons. Myelin is an insulating lipid essential for the rapid communication between neurons. The lack of myelin sheath surrounding the neurons results in poor communication between neurons. In MSA, regions most affected are the neurons within the frontal lobe, which contribute to the control of movement and balance, thus causing the individual to lose balance, develop a tremor, and have a weak gait [4].

MSA has also been shown to cause neurodegeneration within the olivopontocerebellar pathway, striatonigral pathway, and in autonomic nuclei within the brainstem [4]. These systems include the main structures which contribute to the motor skills and autonomic systems of an individual. Therefore, disruption due to neuronal degradation creates faulty communication between these systems, leading to a loss of balance, development of tremors, and unhealthy blood pressure or heart rate.

Studies have suggested that the production of alpha-synuclein proteins is due to an overexpressed gene that produces the transmembrane protein, ABCA8 [5]. ABCA8 is an ATP-binding cassette, functioning to transport lipids across the cellular membrane. ABCA8 is found within the superior frontal lobe where its main role is to transport sphingomyelin from the oligodendrocytes for the production of lipid rafts [4,5]. An overexpression of ABCA8 thus leads to a disruption in lipid homeostasis. Although healthy brains have alpha-synuclein proteins present, the prions within MSA patients are found to be surrounded by more lipids due to homeostasis disruption. Abnormal ABCA8 expression has been shown to increase the production of SM, an essential lipid component formed in oligodendrocytes [6]. The lipid formation results in the gathering and overcrowding of the abnormal alpha-synuclein proteins, which cause the protein to no longer perform its regulatory role, but rather lead to the pathway of neuropathy [6].

Researchers have found that oligodendrocytes largely consist of alpha-synuclein proteins [3]. These proteins are typically responsible for the regulation of synaptic events. However, individuals who suffer from MSA have been found to have irregularly shaped alpha-synuclein proteins within the cytoplasm of the oligodendrocytes [3]. The presence of these proteins causes havoc within the central nervous system by disrupting the proper formation of myelin. The congregation of alpha-synuclein protein disrupts the synthesis of myelin within MSA patients, resulting in poorly insulated axons [3,4]. Without proper insulation, the speed in which messages are sent between neurons is affected. Communication between the cells is no longer under proper control. Within our body, neurotransmitters are released as chemical communicators to regulate the functionality of the body system. Dopamine is released to serve as a precursor for many functions throughout the body. However, the release in the substantia nigra controls motor skills, causing this structure to be of particular interest in neurodegenerative diseases such as Parkinson’s Disease and MSA [7]. A disruption in the communication between neurons in the substantia nigra results in rigid muscles, slurred speech, shuffled gait, and tremors.

In previous studies, the alpha-synuclein human proteins have been paired with the development of Parkinson’s Disease. However, a new strain of the prion has been found among individuals with MSA [2]. The strain is unique to that of Parkinson’s Disease due to its presence in both the neurons and glia of the nigro-striatal area, preventing the production of myelin [3]. Without the proper production of myelin sheath, the neurons remain exposed and therefore are more prone to damage, leading to the degeneration of motor skills and balance that are seen in individuals with MSA. Although researchers have discovered a link between the overexpression of ABCA8 and the rate of myelin production, future studies are to be conducted to solidify the role that the new strain of prion has on the central nervous system. With more research on the prion strain, there is hope to not only treat MSA but also to find a cure for the disease.

References

1. Burn DJ, Jaros E. Multiple system atrophy: cellular and molecular pathology. Molecular pathology. 2001; 54: 419-426.

2. Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH, Glidden DV, Halliday GM, Middleton LT, Gentleman SM, Grinberg LT, Giles K. Evidence for a-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proceedings of the National Academy of Sciences. 2015; 10:1073.

3. Woerman AL, Stohr J, Aoyagi A, Rampersaud R, Krejciova Z, Watts JC, Ohyama T, Patel S, Widjaja K, Oehler A, Sanders DW, Diamond MI, Seeley WW, Middleton LT, Gentleman SM, Mordes DA, Sudhof TC, Giles K, Prusiner SB. Propagation of prions causing synucleinopathies in cultured cells. Proceedings of the National Academy of Sciences. 2015; 112(35): E4949-E4958.

4. Wong JH, Halliday GM, Kim WS. Exploring myelin dysfunction in multiple system atrophy. Experimental neurobiology. 2014; 23(4): 337-344.

5. Bleasel JM, Hsiao JH, Halliday GM, Kim WS. Increased expression of ABCA8 in multiple system atrophy brain is associated with changes in pathogenic proteins. Journal of Parkinson’s Disease. 2013; 3(3): 331-339.

6. Kim WS, Hsiao JH, Bhatia S, Glaros EN, Don AS, Tsuruoka S, Shannon Weickert C, Halliday GM. ABCA8 stimulates sphingomyelin production in oligodendrocytes. Biochem Journal. 2013; 452(3)401-410.

7. Tong J, Ang LC, Williams B, Furukawa Y, Fitzmaurice P, Guttman M, Boileau I, Hornykiewicz O, Kish SJ. Low levels of astroglial markers in Parkinson’s disease: relationship to alpha-synuclein accumulation. Neurobiology of Disease. 2015; 82: 243-253.