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

Benjamin G. Trist, Katherine M. Davies, Veronica Cottam, Sian Genoud, Richard Ortega, Stephane Roudeau, Asuncion Carmona, Kasun De Silva, Valerie Wasinger, Simon J. G. Lewis, Perminder S. Sachdev, Bradley Smith, Claire Troakes, Caroline Vance, Christopher E. Shaw, Safa Al-Sarraj, Helen J. Ball, Glenda Halliday, Dominic J. Hare, Kay L. Double

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)113-127
Number of pages15
JournalActa Neuropathologica
Volume134
Issue number1
DOIs
Publication statusPublished - Jul 2017
Externally publishedYes

Keywords

  • Superoxide dismutase-1
  • Protein aggregation
  • Parkinson’s disease
  • Copper dyshomeostasis
  • Oxidative stress

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