Parkinson's Disease Research
Cell to Cell propagation of amyloid proteins in neurodegenerative diseases
A common feature of most neurodegenerative diseases is the development of misfolded protein aggregates, termed amyloids or amyloid plaques. Although these proteins are different in different diseases (alpha-synuclein in Parkinson's Disease, Amyoid Beta and Tau in Alzheimers disease), numerous lines of research suggests that these proteins can spread between cells in affected regions of the brain and thereby induce a gradually worsening pathology in patients. Our lab seeks to understand the mechanism of this cell to cell transfer of pathological amyloid protiens. Although our work has focused on the mechanism by which amyloid forms of alpha-synuclein can enter "target cells" by inducing the rupture of endocytic vesicles, we have recently observed that this method of invation is common to Tau and Huntington amyloids, revealing this mode of entry as a common feature of other neurodegenerative disease associated amyloid proteins.
We used an imaging based assay to determine that a-syn aggregates, as well as other amyloids, induce vesicle rupture following endocytosis in the images above, as well as the references below. Currently, we are trying to understand how this damage to vesicles impacts the neuronal cell biology and leads to pathogenesis (the development of disease). Based on this picture, we think we are on the right track, since we can see the same things we see in tissue culture in the post-mortem brains of PD patients!
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Freeman D, Cedillos R, Choyke S, Lukic Z, McGuire K, Marvin S, Burrage A, M.Sudholt S, Rana A, O'Connor C, Wiethoff CM, Campbell, EM. Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis PLoS One 2013 May 2, 8:4 PMCID: PMC3636263
Samuel F, Flavin WP, Iqbal S, Pacelli C, Sri Renganathan SD, Trudeau LE, Campbell EM, Fraser PE, Tandon A. Effect of Serine 129 phosphorylation on α-synuclein aggregation, membrane association and internalization. J Biol. Chem. 2015, Dec 30. PMID26719332. PMCID: PMC4813466
Flavin W, Bousset L, Green Z, Chu Y, Skarpathiotis S, Chaney M, Kordower J, Melki R, Campbell EM. Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins, Acta Neuropathologica, published online May 19, 2017. PMID28527044, PMCID in progress