Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson’s disease brain

Abstract

Neuronal loss in numerous neurodegenerative disorders has been linked to protein aggregation and oxidative stress. Emerging data regarding overlapping proteinopathy in traditionally distinct neurodegenerative diseases suggest that disease-modifying treatments targeting these pathological features may exhibit efficacy across multiple disorders. Here, we describe proteinopathy distinct from classic synucleinopathy, predominantly comprised of the anti-oxidant enzyme superoxide dismutase-1 (SOD1), in the Parkinson's disease brain. Significant expression of this pathology closely reflected the regional pattern of neuronal loss. The protein composition and non-amyloid macrostructure of these novel aggregates closely resembles that of neurotoxic SOD1 deposits in SOD1-associated familial amyotrophic lateral sclerosis (fALS). Consistent with the hypothesis that deposition of protein aggregates in neurodegenerative disorders reflects upstream dysfunction, we demonstrated that SOD1 in the Parkinson's disease brain exhibits evidence of misfolding and metal deficiency, similar to that seen in mutant SOD1 in fALS. Our data suggest common mechanisms of toxic SOD1 aggregation in both disorders and a potential role for SOD1 dysfunction in neuronal loss in the Parkinson's disease brain. This shared restricted proteinopathy highlights the potential translation of therapeutic approaches targeting SOD1 toxicity, already in clinical trials for ALS, into disease-modifying treatments for Parkinson's disease.

l‐3,4‐dihydroxyphenylalanine (l‐DOPA) modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha‐synuclein mouse models of Parkinson's disease

“…These including superoxide dismutase‐1 (itself having impaired function in Parkinson's disease; Trist et al . ), DJ‐1 (Biosa et al . ) (also involved in 20S‐proteasome regulation; Moscovitz et al .…”

Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson's disease brain

“…In doing so, we can then narrow the scope of future proteomic studies targeting these specific subcellular compartments using high-throughput shotgun proteomics methods, 33 which are currently underway in our laboratory. In addition, as both a-synuclein and SOD1 are demonstrated to aggregate in Parkinson’s disease, 34 determining the subcellular fraction where these metal changes occur allows us to then identify whether these alterations are associated with the soluble forms of these proteins, or the aggregated form which would reside in the insoluble fraction.…”

“…The insoluble fraction of the Parkinson’s disease SN is also likely to include a smaller proportion by mass of small insoluble proteinaceous deposits, including Lewy bodies 24 and SOD1 aggregates. 34 While metals have been suggested to induce α-synculein oligomerisation and aggregation in vitro , 38 it is unclear whether Lewy bodies retain metal ions. We recently demonstrated that SOD1 aggregates recently identified in Parkinson’s disease share pathological similarities with the deposited protein in familial amyotrophic lateral sclerosis spinal cord and SN, 34 and this class of aggregate has been shown to be deficient in Cu.…”

“…34 While metals have been suggested to induce α-synculein oligomerisation and aggregation in vitro , 38 it is unclear whether Lewy bodies retain metal ions. We recently demonstrated that SOD1 aggregates recently identified in Parkinson’s disease share pathological similarities with the deposited protein in familial amyotrophic lateral sclerosis spinal cord and SN, 34 and this class of aggregate has been shown to be deficient in Cu. 39 The different populations of insoluble protein aggregates in degenerating regions of the Parkinson’s disease brain may thus display metal associations that differ from that in the normal soluble protein, a hypothesis that could be tested using, for example, biochemical imaging analysis at the single aggregate level.…”

“…Recent data has demonstrated increased SOD1 protein levels, yet a marked decrease in enzymatic activity in the Parkinson’s disease SN, 34 proposed to result due to a lack of an essential Cu-association with this protein. Given the key bioactive role for Cu-mediated antioxidant activity in the brain, Cu modulation is a potential therapeutic avenue for Parkinson’s disease, 59 and the repurposed positron emission tomography agent copper(II) diacetyl bis ( N (4)-methylthiosemi-carbazonato), or Cu II (atsm), has shown efficacy in transgenic and neurotoxin mouse models of Parkinson’s disease.…”