UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Propagation of Cu/Zn superoxide dismutase misfolding via tissue-derived extracellular vesicles in Amyotrophic Lateral Sclerosis Fernando, Sarah


Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease wherein motor neurons progressively degenerate over time, and pathology spreads spatiotemporally throughout the neuroaxis. Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are linked to inherited cases of ALS, and misfolded SOD1 protein has been reported in neural tissues from all ALS subtypes. We have previously shown that human wild-type SOD1 (HuWTSOD1) in cultured HEK cells can be induced to misfold by transgenically-expressed mutant SOD1, and that cell-to-cell transmission of HuWtSOD1 misfolding can occur in vitro. However, the mechanism(s) by which misfolded SOD1 could be propagated in vivo remain unknown. In this study, we investigated the capability of central nervous system (CNS) tissue-derived exosomes and microvesicles to propagate SOD1 misfolding. The overarching hypothesis of the work is that CNS tissue-derived EVs from ALS mouse models bear misfolded SOD1 cargo, and can induce SOD1 misfolding in recipient cultured cells. The hypothesis was investigated using the following specific aims: 1) Isolate and characterize CNS tissue-derived EVs from ALS mouse models 2) Investigate the presence and localization of misfolded SOD1 in isolated EVs 3) Examine capability of ALS mouse model tissue-derived EVs to propagate SOD1 misfolding to cell culture systems, and 4) Explore physiological relevance of findings using EVs isolated from human ALS patients. Using primary spinal motor neuron and glial cultures from HuWTSOD1 transgenic mice, and a misfolded SOD1 conformation-specific antibody, we show for the first time that both CNS-derived EV subtypes are capable of transmitting SOD1 misfolding to recipient cells. Our study provides novel evidence consistent with a potential role of CNS-derived extracellular vesicles in human ALS, and highlights the ability to use the more abundant microvesicle population to investigate the functional effects of EVs in protein misfolding diseases.

Item Citations and Data


Attribution-NonCommercial-NoDerivatives 4.0 International