Objective: To characterize (1) a novel association between superoxide dismutase 1 (SOD1) aggregation and neuronal loss in the Parkinson’s disease (PD) brain and (2) the biophysical similarities of this pathology with SOD1 inclusions in motor neurons in familial and sporadic amyotrophic lateral sclerosis (ALS).

Background: Protein aggregation is a central theme within neurodegenerative cascades in many neurological disorders and is a target for the development of disease-modifying therapies. Abnormal aggregation of α-synuclein protein into Lewy bodies is linked to neuronal loss in PD; however the end-stage distributions of Lewy pathology and neuronal loss are grossly misaligned. We have identified a novel SOD1 immunopositive proteinaceous aggregate in regions of significant neuronal loss in the PD brain.

Methods: All experiments employed human post-mortem tissues from PD and age-matched control brains. Immunohistochemistry was used to characterize the composition and structure of SOD1 aggregates, and blinded interrater quantitation to characterize their distribution throughout the PD and control brain. Non-denaturing isoelectric focusing was utilized to identify changes in the isoelectric point of SOD1 protein, indicative of SOD1 protein conformation.

Results: Protein aggregates immunopositive for SOD1 were significantly more abundant in degenerating regions of the PD brain (>5 fold increase in substantia nigra, >2.5 fold increase in locus coeruleus), compared with non-degenerating PD brain regions or in control brains. Unlike Lewy pathology, these aggregates contain no α-synuclein. Similar to SOD1-immunopositive pathology in ALS, these aggregates contained significant amounts of SOD1, copper chaperone for SOD1 and ubiquitin, and were negative for Congo-Red and Thioflavin-S dyes. A positive isoelectric point shift in one isoform of SOD1 was also observed in the PD, compared with control brain.

Conclusions: Our data demonstrates that SOD1 protein aggregates in the PD brain and that these aggregates are present in significant quantities only in regions of neuronal loss. Considering the accepted role of SOD1 pathology in neuronal loss in ALS, we suggest a role for this novel pathology in neuronal vulnerability in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sod1-aggregation-a-pathological-link-between-parkinsons-disease-and-amyotrophic-lateral-sclerosis/