Imagine building a brand-new Lego set. In the box are clear instructions and all the required pieces to assemble the desired structure. How difficult would it be if the manufacturer, substituted one incorrect piece? In simple terms, it might have very little impact, but it could also dramatically change the structural integrity. In biochemistry, the production of proteins is like building a Lego structure and a mutation is like the inclusion of a wrong piece. Lego blocks, like amino acids, are highly specific, and using the correct type of piece is essential to building a functional protein.
Interestingly, several common and severe diseases are caused by substitution mutations where one type of amino acid is substituted for another amino acid. Some of these conditions include Wilson’s Disease, Cystic Fibrosis, and Parkinson’s Disease. According to recent approximations, about 0.2% of individuals in Western Europe including nearly 4% of individuals over eighty years of age in a similar population are diagnosed with Parkinson’s Disease each year (Davie 2008). The condition mainly affects the central nervous system causing symptoms such as difficulty initiating movement, muscular rigidity, and other behavioral abnormalities (Spencer et. al. 2014). While this condition can affect individuals sporadically, primary risk factors include hereditary and environmental factors such as chemical exposure to certain wood preservatives and pesticides in some rural areas (Davie 2008). Contact with these chemicals can cause genetic changes that lead to an amino acid mutation in the protein structure that dramatically alters its physical and chemical properties. Namely, the mutated α-synuclein protein, the affected protein, has a lower solubility in water which leads to small protein accumulations, known as Lewy bodies, throughout the brain (Davie 2008). A recent 2016 study, α‐Synuclein Conformational Antibodies Fused to Penetratin Are Effective in Models of Lewy Body Disease, suggests that treatments for Parkinson’s Disease may be most effective using a synthetic protein-like agent delivered by a carrier protein. The authors, Brian Spencer, Ph.D., Stephanie Williams Ph.D., and Edward Rockenstein, Ph.D. and their research staff, work jointly at The University of California, San Diego, and Arizona State University and published the article which appeared in the Annals of Clinical Neurology a publication of the American Neurological Association.
The primary aims of the 2016 study were to assess the efficacy of an antibody-drug on decreasing alpha-synuclein accumulations and evaluate the best method of delivery (Spencer et. al.). To investigate this, researchers prepared three types of potential drugs labeled as 10H, D5, and D10 which are simply codenames of alpha-synuclein antibody variants. Additionally, a carrier protein known as a “Penetratin” protein, which guides substrates through membranes to receptors, was isolated for the experiment to determine if it would be an effective drug delivery method. For the test tube studies, the research group selected a cell line that overexpresses the mutated α-synuclein protein, added the antibody compound, and incubated the sample under parameters similar to the human brain. To analyze how each drug combination performed, they used a special instrument to measure the light absorbance through each sample. Additionally, to evaluate the carrier protein in a biological system, scientists used an animal study with twenty-four mice with a genetic mutation that caused similar effects to Parkinson’s Disease. Then, scientists injected antibody-drug types with and without carrier proteins into the hippocampus. To measure the results the researchers prepared brain slice specimens and analyzed them with a special microscopy technique.
Dr. Spencer’s research group found significant support for the effectiveness of two of their experimental drugs, D5 and 10H. The group first determined that all the experimental drugs interacted with small aggregates of mutated α‐synuclein. However, D10 also reacted with un-accumulated forms of α‐synuclein which is the most abundant form found in the brain. As a result, researchers believe that almost all of the D10 drug is consumed before it can even reach the harmful Lewy bodies (Spencer et. al. 2016). Additionally, the use of the D5 and 10H drugs seemed to reverse the severity of symptoms among the treated mice. After identifying that the two drugs decrease agglutinations, scientists performed behavioral tests by timing how fast each mouse could remove an adhesive sticker from its snout. The mice treated with the D5 and 10H drug types showed a nearly twofold reduction in the time required to complete the task (Spencer et. al. 2016). This suggests that neurodegenerative effects caused by Lewy bodies may be reversible and D5 and D10 drug types may be effective treatments. Finally, the group tested the efficacy of a carrier protein that they believed would guide the protein through membrane diffusion because it has permeable properties. As expected, the D5 and 10H drug molecules enhanced with the “Penetratin” protein reduced the accumulation of α‐synuclein in the mice trials. Interestingly, the D10 molecules enhanced with “Penetratin” did not alleviate aggregations likely because the D10 molecule interacts with the more abundant and non-aggregated α‐synuclein form (Spencer et. al. 2016).
Although the Spencer study shows exciting results, patients and families should not be overly enthused by the findings. The application of their results is very limited because the experiments were only tested in the lab and on lower-order animals – not in human subjects. Although required for later-stage research, these types of procedures often ignore the complexity of biological systems and lower-order animals like mice and gerbils do not translate directly to higher-order species like humans. Additionally, the researchers acknowledge their potential conflicts of interest at the end of the paper. Following their discussion, they disclose that the university they work for, Arizona State University, is filing patents for each of the drug types (Spencer et. al., 2016). While filing patents for promising molecules is standard practice, it is critical to recognize the potential monetary benefit should this become an approved and mass-produced drug. Consequently, the paper might exaggerate claims and the public should remain cautious of these results: especially in the pre-clinical experiments.
The recent experiments with α‐synuclein antibodies show meaningful progress in the fields of neurology and pharmaceutical design. Researchers from Arizona State University and the University of California at San Diego collaborated to test the efficacy of the newly synthesized drugs for Parkinson’s Disease and other neurodegenerative disorders which were derived to model α‐synuclein antibodies. Experiments included culture samples and animal trials which showed positive effects among two of the three drugs. A future study might seek to classify disease progression or attempt to understand the specific roles and mechanisms of synuclein-type proteins. The community should understand that the research presented here is a small step in managing such a highly complex disease, so the knowledge acquired cannot just be crudely applied among human populations. As more research in this field appears, scientists will gain perspective and contextualize this into the greater body of natural science and medicine.
References
An introduction to molecular dynamics [ video ]. 2012 October 29, 4:11 minutes. YouTube, Science4all. [accessed 21 September 2021]. https://www.youtube.com/watch?v=lLFEqKl3sm4.
Copyright free science laboratory // research stock footage // microscope stock footage [ video ]. 15 November 2020, 2:15. YouTube, Copyright Free Stock Video. [accessed 21 September 2021]. Available from: https://www.youtube.com/watch?v=xKSlP4rkXsY.
Davie CA. 2008. A review of Parkinson’s disease. British Medical Bulletin. [accessed 2021 Sep 5];86(1):109–127. https://academic-oupcom.libproxy.lib.unc.edu/bmb/article/86/1/109/379503.
Doctor and patient HD stock video |free stock footage |free HD videos – no copyright |channel PMI [ video ]. 2021 February 27, 3:19 minutes. YouTube, Channel PMI – Free Stock Video. [accessed 21 September 2021]. https://www.youtube.com/watch?v=DmcqxA_vhdI.
Doctor, discussion, patient, doctor’s office [ video ]. 2021 April 13, 0:20 min. YouTube, Artgrid – Stock Footage. [Accessed 21 September 2021]. https://www.youtube.com/watch?v=Qdv1P-3glLU.
Inside Alzheimer’s disease [ video ]. 2017 January 3, 4:20 minutes. YouTube, Nature Video. [accessed 21 September 2021]. https://www.youtube.com/watch?v=zTd0-A5yDZI.
Laboratory stock footage | 4k royalty-free stock footage [ video ]. 2020 September 3, 1:06 minutes. YouTube, Creatorflow – Video & Music for Content Creators. [accessed 21 September 2021]. Available from: https://www.youtube.com/watch?v=GsIzRIrknFo.
Scientists talking about research |group scientist| free video [ video ]. 2021 June 9, 0:20 minutes. YouTube, No Copyright Free Video. [accessed 21 September 2021]. https://www.youtube.com/watch?v=3YfdmSgmwBA.
Sincere feeling [ audio ]. 2021, 2:18 minutes. TribeOfNoise, KonovalovMusic. [accessed 21 September 2021]. https://prosearch.tribeofnoise.com/search/index?titles%5B0%5D%5Bid%5D=33574.
Spencer B, Emadi S, Desplats P. 2014. ESCRT-mediated uptake and degradation of brain-targeted α-synuclein single-chain antibody attenuate neuronal degeneration in vivo. American Society of Gene and Cell Therapy. [accessed 2021 Sep 5];22(10):1753–1767. https://reader.elsevier.com/reader/sd/pii/S1525001616307808?token=775BDE903459A882595944BF87B806FD505EDC2B2E1F72C45688A461FA005444DC78DF82238F9258BB308BE88561311D&originRegion=us-east-1&originCreation=20210905222529.
Spencer B, Williams S, Rockenstein E, et. al. 2016. α ‐Synuclein conformational antibodies fused to Penetratin are effective in models of Lewy body disease. Annals of Clinical and Translational Neurology. [accessed 2021 Sep 5];3(8):588–606. https://www.proquest.com/docview/1970516424/fulltextPDF/AA1619C95707468DPQ/1?accountid=14244.
Tail and scruff handling of mice [ video ]. 2013 August 27, 1:14 minutes. YouTube, Londholt Kommunikation. [accessed 21 September 2021]. https://www.youtube.com/watch?v=Gs-ebUnPQEc.
Featured Image Source:
Redvanly T and Lott B. 2020 July 13. 1XQ8 Single Frame Stepwise α-Synuclein Protein Trajectory [digital photograph]. Thomas Redvanly and Brittany Lott. [accessed 2021 September 26].