Have you heard of a case of someone affected by a Lewy Body? Lewy Bodies are poorly formed proteins that come together and form nonfunctional aggregates. These aggregates typically appear in some neurodegenerative disorders like Parkinson’s Disease. In the paper “Endocytic Vesicle Rupture is a Conserved Mechanism of Cellular Invasion by Amyloid Proteins”, Campbell et. al. explore the underlying mechanisms behind the creation of misfolded proteins and how they can propagate in a human nervous system with very damaging effects. In their lab’s experiments they found that Alpha-Synuclein requires the ability to break open vesicles as a means of propagation. Amyloid aggregates are endocytosed into cells. However, once inside the cell, they begin to instigate vesicle rupturing within cells. The research team used various modified versions of Alpha Synuclein and found that this rupturing takes place across all variations (Campbell 2017). Cells can either try to address this problem with a lysosome (an organelle within the cell tasked with destroying possible intruders) or push the aggregate out of the cell. In both of these scenarios, the aggregate eventually spreads either through the eventual destruction of the host cell or the spread of the aggregate to another cell. This study points to how vesicle rupturing is a key way in which aggregates function, in essence, it is a biologically inevitable process across malformed Alpha Synucleins..
Other labs are also intrigued at understanding how Alpha Synuclein works within a given cell. For example, a study entitled, “The Localization of Alpha-Synuclein in the Endocytic System” (Fakhree 2021) worked to uncover what were the associated proteins that were typically found alongside Alpha-Synuclein after endocytosis into the cell. They identified a key protein, Caveolin, which is often found in similar locations within the endocytic pathway of the cell. Caveolin plays a major role in the proper functioning of internal cell vesicles (Cohen et. al. 2004). According to Fakhree et. al. their finding has major implications because, “The structural colocalization between Alpha Synuclein and Caveolin indicates there is a direct link between Alpha Synuclein function and vesicle mistrafficking” (Fakhree 2021). Fakhree et. al.’s investigation provides future clues as to how Alpha Synuclein functions with other proteins to produce dilapidating effects in the cell.
Both papers work together to create a more cohesive picture of how Alpha Synuclein can affect the endocytic pathway. This wider understanding of where and how Alpha Synuclein works can be useful in the devising of treatment options. For example, in my opinion, future studies could be conducted with genetically mutated forms of Caveolin as a possible way of attenuating the effects of Alpha Synuclein. Additionally, a collaboration between the two labs could propose a study in which Caveolin could be mutated to assist anaplerotically in the emission of an apoptotic signal in response to contact with a dysfunctional Alpha Synuclein aggregate. I am unsure as to the feasibility or practicality of these hypothetical studies, the example is simply to show that there is an overlap in the studies. These articles show that there is greater research potential to be explored with regard to endocytic vesicle interactions with Alpha Synuclein.
Works Cited
Cohen AW, Razani B, Schubert W, Williams TM, Wang XB, Iyengar P, Brasaemle DL,
Scherer PE, Lisanti MP. Role of caveolin-1 in the modulation of lipolysis and lipid
droplet formation. Diabetes. 2004 May;53(5):1261-70. doi: 10.2337/diabetes.53.5.1261. PMID: 15111495.
Fakhree MAA, Konings IBM, Kole J, Cambi A, Blum C, Claessens MMAE. The
Localization of Alpha-synuclein in the Endocytic Pathway. Neuroscience. 2021
Mar 1;457:186-195. doi: 10.1016/j.neuroscience.2021.01.017. Epub 2021 Jan 20.
PMID: 33482328.
Flavin WP, Bousset L, Green ZC, Chu Y, Skarpathiotis S, Chaney MJ, Kordower JH, Melki
R, Campbell EM. Endocytic vesicle rupture is a conserved mechanism of cellular
invasion by amyloid proteins. Acta Neuropathol. 2017 Oct;134(4):629-653. doi:
10.1007/s00401-017-1722-x. Epub 2017 May 19. PMID: 28527044.
No comments:
Post a Comment