Investigation of Superoxide Dismutase 1 in Neurodegeneration

This project focuses on the role of superoxide dismutase 1 (SOD1) in synucleinopathy-associated neurodegeneration, specifically idiopathic Parkinson’s disease (PD). The central hypothesis guiding this work is that aggregated SOD1 species are correlated with misfolded alpha-synuclein (SNCA) aggregates in human idiopathic PD brain and that these SOD1 aggregates act in concert with misfolded SNCA to exacerbate disease progression. Building on expertise in protein folding, abnormal protein conformers, and biomarkers, the project is organized around two complementary aims designed to interrogate the presence, relationship, and pathogenic synergy of SOD1 and SNCA misfolding across human tissue and animal models. The first aim concentrates on a detailed analysis of SOD1 and SNCA misfolding in human PD brain samples.

This component of the work seeks to characterize the biochemical and histopathological relationships between SOD1 aggregates and established SNCA pathology in idiopathic PD. Using human postmortem tissue, the investigation will assess whether SOD1 aggregation co-localizes with SNCA-positive inclusions, whether particular brain regions show stronger co-occurrence, and whether biochemical signatures of SOD1 misfolding correlate with measures of SNCA aggregation or with indicators of neurodegeneration. By focusing on human samples, the aim addresses disease relevance directly and seeks to establish whether SOD1 aggregation is a common or sporadic feature in idiopathic PD, and whether its presence associates with disease severity or regional vulnerability. The second aim extends findings from human tissue into experimental mouse models to explore interaction and disease progression. In mice, the project will interrogate whether the presence of SOD1 aggregates accelerates or modifies SNCA-driven pathology and clinical features. Experimental designs will examine whether co-expression or induction of misfolded SOD1 influences SNCA aggregation kinetics, propagation, neuronal dysfunction, or behavioral phenotypes relevant to PD. This translational axis tests causality and mechanism: if SOD1 aggregation contributes to SNCA-mediated neurodegeneration, then manipulations that alter SOD1 folding or aggregation should impact the course of synucleinopathy in vivo. Across both aims, the work integrates biochemical assays and neuropathological analysis to evaluate aggregate species, their distribution, and their effects on tissue integrity.

The project’s focus on abnormal protein conformers and biomarkers positions it to not only elucidate mechanistic cross-talk between two proteinopathies but also to identify potential molecular readouts that could inform future diagnostic or therapeutic strategies. By explicitly assessing SOD1–SNCA interactions in human brain and testing their functional relevance in mouse models, Leavens’ project aims to bridge observational pathology with mechanistic insight. Ultimately, this investigation seeks to clarify whether SOD1 aggregation is a contributing factor to idiopathic PD pathogenesis via synergistic misfolding with SNCA. Establishing such a relationship would broaden understanding of molecular mechanisms in PD and could open new avenues for targeting protein misfolding interactions in neurodegenerative disease.