Parkinson-like wild-type superoxide dismutase 1 pathology induces nigral dopamine neuron degeneration in a novel murine model Original paper

What was reviewed?

The review examines the pathology of wild-type superoxide dismutase 1 (SOD1) in Parkinson’s disease (PD), focusing on how altered post-translational modifications (PTMs) and metal-binding deficiencies contribute to misfolding and aggregation of SOD1 in the substantia nigra pars compacta (SNc). This pathology is observed in PD patients despite the absence of SOD1 gene mutations, with structural and functional alterations leading to the degeneration of nigral dopamine neurons. The review explores the biochemical mechanisms behind SOD1 dysfunction, including copper deficiency and the influence of elevated SOD1 protein levels. Furthermore, it introduces a novel mouse model, the SOCK mouse, engineered to simulate the biochemical conditions observed in PD and to study the relationship between wild-type SOD1 pathology and dopamine neuron health. The model’s relevance in understanding PD etiology is emphasized, particularly in exploring potential therapeutic targets for modifying SOD1-related pathologies.

Who was reviewed?

The review does not focus on individual human or animal subjects but instead discusses existing studies on the impact of SOD1 pathology in Parkinson’s disease. It examines post-mortem brain tissue from PD patients and utilizes animal models, particularly the novel SOCK mouse model, to investigate the role of misfolded SOD1 in neurodegeneration. The study particularly focuses on the nigral dopamine neurons, which are the most vulnerable in PD, and how their degeneration is linked to abnormal SOD1 behavior.

What were the most important findings?

The key findings of this review center on the discovery of altered post-translational modifications in SOD1 within the SNc of Parkinson’s disease patients. These modifications, such as decreased copper binding, atypical oxidation, and glycation of key amino acid residues, were associated with SOD1 misfolding, aggregation, and dysfunction. The review also highlights that the SOCK mouse model, engineered to replicate a decrease in copper availability and elevated wild-type SOD1 levels, develops progressive dopamine neuron loss in the SNc. This model mimics the pathological conditions observed in PD patients, such as misfolded SOD1 and dopamine neuron degeneration, in the absence of α-synuclein deposition. Importantly, the model did not show spinal cord motor neuron degeneration, distinguishing it from other transgenic SOD1 models. The review suggests that copper deficiency and SOD1 overexpression act together to precipitate the accumulation of disordered SOD1, leading to neuron dysfunction and degeneration, thus providing new insights into Parkinson’s pathogenesis.

What are the greatest implications of this review?

The greatest implications of this review are centered on the identification of wild-type SOD1 pathology as a potential novel target for Parkinson’s disease therapeutics. The findings suggest that correcting the post-translational modifications of SOD1, particularly those involving copper binding, could mitigate the misfolding and aggregation of SOD1 in the brain. The SOCK mouse model provides a valuable tool for further understanding the mechanisms by which SOD1 dysfunction contributes to dopamine neuron degeneration and could be pivotal in testing potential drug candidates aimed at modifying SOD1 behavior. This review advocates for targeting the biochemical alterations in SOD1 to develop disease-modifying treatments for Parkinson’s disease, marking an important step forward in addressing the unmet therapeutic needs in this field.