47 Fei Wang – Protein Misfolding-Associated Neurodegenerative Diseases
Satveer Sangha; Bardia Yasari; and Zoë Soon
Fei Wang, PhD
Dr. Fei Wang is an assistant professor at the Mitchell Centre for Alzheimer’s Disease and Brain Disorders (Wang, F. 2023). Dr. Wang’s research is mainly focused on protein misfolding-associated neurodegenerative diseases (Wang, F. 2023). His research interests and goals included further investigating neurotoxic mechanisms that result in protein misfolding-associated neurodegenerative diseases (Wang, F. 2023). Dr. Wang has researched prion diseases, neurodegenerative disorders that severely impact people and animals, which is caused by the misfolding of a prion protein (PrPC) into a pathogenic prion protein (PrPSc) (Wang et al. 2018). Dr. Wang investigated the infectivity of both undigested and proteinase K digested recombinant prions, leading to quite the same results of infectivity (Wang et al. 2018). Another publication by Dr. Wang explains prion diseases are infectious protein misfolding disorders that are the only protein misfolding disorders that occur naturally. Dr. Wang and Dr. Ma provided a ‘protein-only hypothesis’ which demonstrated that a protein can replicate itself without nucleic acid (Ma & Wang, 2014).
In more detail Transmissible spongiform encephalopathies (TSEs), also called prion diseases, are fatal neurodegenerative disorders with sporadic, inherited, or acquired forms. They share characteristics like late-age onset, misfolded protein buildup in the nervous system, and neurodegeneration with disorders like Alzheimer’s. Uniquely, prion disease is naturally infectious due to misfolded proteins and can spread between species. The ‘protein-only hypothesis’ posits that a prion causes neuronal damage by converting normal proteins into misfolded proteins which accumulate inside cells leading to cellular dysfunction and cellular death.
Exploring the scrapie agent’s chemistry began after confirming its transmissibility in the 1930s. Initially believed viral, evidence suggested otherwise. We learn later that these prions are not infectious but can cause disease if consumed, and at times can occur spontaneously.
Various scientists tried to use radiation therapy to break down these proteins but witnessed an unusual radiation resistance from these prions. This suggest that the agent could be a self-replicating protein, because no matter how much they’d breakdown, many more would be made again. This idea was expanded by Griffith in the ‘protein-only hypothesis.’
Dr. Fei Wang studied the works of Stanley Prusiner who worked to figure out how scrapie infection spreads. They discovered that a special part of a hamster’s brains, filled with a tough protein around 27-30 kDa, held the infection.
The accumulation of pathogenic prion protein (PrPSc) leads to damage in areas like the cerebral cortex, thalamus, and basal ganglia, resulting in some of the characteristics seen in affected brains.
In 1982, Prusiner came up with the word ‘prion’ for these “small infectious proteins that don’t change like genetic material.” The clean version, PrP27-30 or PrP, led to finding the Prnp gene that makes the normal prion protein (PrPC). This PrPC is in the nervous system and some other tissues and is able to stick to cells with a special anchor.
Both PrPC and the disease-related PrP27-30 (PrPSc) have the same building blocks but different shapes. PrPC is flexible and is able to dissolve in water and break down easily. On the other hand, PrPSc is stiff, clumps together, and is a bit harder to break down. PrPSc is linked to the disease process.
In various different studies of Alzheimer’s Disease, Amyloid beta (Aβ) proteins were also under investigation. They usually cause very similar problems that prions also cause such as protein clumping, neuron dysfunction, and brain structure alteration, but more research is needed to make sense of the connections between the two.
As a brief introduction to Amyloid beta (Aβ) it’s important to note that it’s a protein fragment that plays an important role in the development of Alzheimer’s disease and that the precursor of this protein is amyloid precursor protein (APP). In Alzheimer’s Disease, Amyloid beta (Aβ) can accumulate in the brain and form abnormal clumps known as amyloid plaques, which can interfere with normal communication between brain cells and trigger inflammation, leading to neurodegeneration and cognitive decline.
Fun Facts:
Dr. Fei Wang completed his Bachelors in Science in Microbiology at Nankai University, China; later he received a PhD in biochemistry from The Ohio State University (“Fei Wang, PhD”, n.d.). He is the recipient of multiple grants including: The CJD Foundation Grant, the Strides for CJD Grant, and The Katie Dopirak Memorial Grant (“Fei Wang, PhD”, n.d.). Further on, Dr. Wang received the position as a post-doctoral research fellow at the University of Texas Health Science Center and later joined the Mitchell Center for Alzheimer’s Disease and Brain Disorders as an assistant professor in 2021 (Wang, F. 2023).
References
– Ma, J., & Wang, F. (2014). Prion disease and the ‘protein-only hypothesis.’ Essays in Biochemistry, 56, 181–191. https://doi.org/10.1042/bse0560181
-Wang, F. (2023, August 3). Fei Wang, Phd. Department of Neurology. https://med.uth.edu/neurology/2022/10/31/fei-wang-phd/%C2%A0
– Wang, F. (2022, December 15). Fei Wang, Phd. Creutzfeldt-Jakob Disease Foundation. https://cjdfoundation.org/fei-wang-phd
– Wang, F., Wang, X., Abskharon, R., & Ma, J. (2018). Prion infectivity is encoded exclusively within the structure of proteinase K-resistant fragments of synthetically generated recombinant prpsc. Acta Neuropathologica Communications, 6(1). https://doi.org/10.1186/s40478-018-0534-0
