Accumulation of dysfunctional SOD1 protein in Parkinson’s disease is not associated with mutations in the SOD1 gene

Double, Kay L.; Fifita, Jennifer A.; Freckleton, Sarah; Hare, Dominic J.; Lewis, Simon J.G.; Halliday, Glenda M.; Blair, Ian P.; Double, Kay L.

doi:10.1007/s00401-017-1779-6

Cited by 23 publications

(21 citation statements)

References 11 publications

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“…H 2 O 2 buildup in the PD SNc is compounded by a significant reduction in the levels and function of catalase in this brain region, compared with that in the healthy aged brain (Ambani, Van Woert, & Murphy, ). In addition to H 2 O 2 , O 2 − clearance in the PD SNc may be diminished due to SOD1 enzymatic dysfunction and aggregation (Trist et al, ; Trist, Fifita, et al, ; Trist, Hare, & Double, ), which is also associated with neuronal copper deficiency and misfolded α‐synuclein in this brain region (Helferich et al, ).…”

Section: Antioxidant Dysfunctionmentioning

confidence: 99%

Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease

2019

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Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease‐modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady‐state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.

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Section: Antioxidant Dysfunctionmentioning

confidence: 99%

Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease

2019

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“…Aggregation of TDP-43 or SOD1 are observed in ALS (Brown, 1998; Neumann et al, 2006). Recent data demonstrate, however, that aggregation of one particular protein is not specific for one disease (e.g., Cisbani et al, 2017; Trist et al, 2018). Under physiological conditions, the ubiquitin proteasome system (UPS), autophagosomes and chaperone activity ensure the clearance of protein aggregates (Stroo et al, 2017).…”

Section: Protein Aggregationmentioning

confidence: 99%

The Contribution of Iron to Protein Aggregation Disorders in the Central Nervous System

et al. 2019

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The homeostasis of iron is of fundamental importance in the central nervous system (CNS) to ensure biological processes such as oxygen transport, mitochondrial respiration or myelin synthesis. Dyshomeostasis and accumulation of iron can be observed during aging and both are shared characteristics of several neurodegenerative diseases. Iron-mediated generation of reactive oxygen species (ROS) may lead to protein aggregation and cellular toxicity. The process of misfolding and aggregation of neuronal proteins such as α-synuclein, Tau, amyloid beta (Aβ), TDP-43 or SOD1 is a common hallmark of many neurodegenerative disorders and iron has been shown to facilitate protein aggregation. Thus, both, iron and aggregating proteins are proposed to amplify their detrimental effects in the disease state. In this review, we give an overview on effects of iron on aggregation of different proteins involved in neurodegeneration. Furthermore, we discuss the proposed mechanisms of iron-mediated toxicity and protein aggregation emphasizing the red-ox chemistry and protein-binding properties of iron. Finally, we address current therapeutic approaches harnessing iron chelation as a disease-modifying intervention in neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis.

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“…3 Altered Zn 2+ and Cu +/2+ binding to wildtype SOD1 is also suggested to be involved in similar pathogenic pathways in sporadic ALS, 35 consistent with aggregation of wildtype SOD1 in PD. 36 We examined the ratio of Cu to Zn in SOD1 aggregates (Fig. 3) to determine if altered metal stoichiometry associated Fig.…”

Section: Impaired Cu-binding Of Sod1 Aggregates In the Pd Brainmentioning

confidence: 99%

Simultaneous structural and elemental nano-imaging of human brain tissue

et al. 2020

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Accumulation of dysfunctional SOD1 protein in Parkinson’s disease is not associated with mutations in the SOD1 gene

Cited by 23 publications

References 11 publications

Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease

Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease

The Contribution of Iron to Protein Aggregation Disorders in the Central Nervous System

Simultaneous structural and elemental nano-imaging of human brain tissue

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