Wild-type Cu/Zn superoxide dismutase stabilizes mutant variants by heterodimerization

Weichert, Anna; Besemer, Anna S.; Liebl, Martina P.; Hellmann, Nadja; Koziollek-Drechsler, Ingrid; Ip, Philbert; Decker, Heinz; Robertson, Janice; Chakrabartty, Avijit; Behl, Christian; Clement, Albrecht M.

doi:10.1016/j.nbd.2013.10.027

Cited by 16 publications

(26 citation statements)

References 61 publications

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“…Despite considerable study, the mechanism that confers to SOD1 aggregates cell toxicity is still undefined. It has been hypothesized that mutant SOD1 soluble species are responsible for the disease onset (Zetterström et al, 2007 ; Karch et al, 2009 ) being, indeed, more toxic than insoluble aggregated SOD1 forms (Zetterström et al, 2007 ; Brotherton et al, 2012 ; Weichert et al, 2014 ). The intriguing problem of SOD1 aggregation is further complicated by the fact that experimental studies have been largely performed in lines of transgenic animals (or motor neuronal cells) with strong, although heterogeneous, overexpression of mutant proteins required to display pathological phenotype.…”

Section: Accumulation Of Mutant Sod1 In the Mitochondrial Intermembramentioning

confidence: 99%

SOD1 misplacing and mitochondrial dysfunction in amyotrophic lateral sclerosis pathogenesis

Tafuri

Ronchi

Magri

et al. 2015

Front. Cell. Neurosci.

122

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Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease presenting as sporadic (sALS) or familial (fALS) forms. Even if the list of the genes underlining ALS greatly expanded, defects in superoxide dismutase 1 (SOD1), encoding the copper/zinc SOD1, still remain a major cause of fALS and are likely involved also in apparently sporadic presentations. The pathogenesis of ALS is still unknown, but several lines of evidence indicate that the mitochondrial accumulation of mutant SOD1 is an important mechanism of mitochondrial dysfunction, leading to motor neuron pathology and death. The intramitochondrial localization of mutant SOD1 is debated. Mutant SOD1 might accumulate inside the intermembrane space (IMS), overriding the physiological retention regulated by the copper chaperone for superoxide dismutase (CCS). On the other hand, misfolded SOD1 might deposit onto the outer mitochondrial membrane (OMM), clumping the transport across mitochondrial membranes and engaging mitochondrial-dependent cell apoptosis. The elucidation of the mechanisms ruling SOD1 localization and misplacing might shed light on peculiar ALS features such as cell selectivity and late onset. More importantly, these studies might disclose novel targets for therapeutic intervention in familial ALS as well as non-genetic forms. Finally, pharmacological or genetic manipulation aimed to prevent or counteract the intracellular shifting of mutant SOD1 could be effective for other neurodegenerative disorders featuring the toxic accumulation of misfolded proteins.

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Section: Accumulation Of Mutant Sod1 In the Mitochondrial Intermembramentioning

confidence: 99%

SOD1 misplacing and mitochondrial dysfunction in amyotrophic lateral sclerosis pathogenesis

Tafuri

Ronchi

Magri

et al. 2015

Front. Cell. Neurosci.

122

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“…SOD1 G85R and SOD1 G93A represent two classes of SOD1 mutations. The SOD1 G93A mutation shares many biophysical and biochemical properties of wild-type SOD1 despite it is structurally different to SOD1 WT 30 31 . In contrast, dismutase activity of SOD1 G85R in tissues is not detectable 32 33 .…”

Section: Discussionmentioning

confidence: 99%

Low-frequency magnetic fields do not aggravate disease in mouse models of Alzheimer's disease and amyotrophic lateral sclerosis

Liebl

Windschmitt

Besemer

et al. 2015

Sci Rep

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Low-frequency magnetic fields (LF-MF) generated by power lines represent a potential environmental health risk and are classified as possibly carcinogenic by the World Health Organization. Epidemiological studies indicate that LF-MF might propagate neurodegenerative diseases like Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS). We conducted a comprehensive analysis to determine whether long-term exposure to LF-MF (50 Hz, 1 mT) interferes with disease development in established mouse models for AD and ALS, namely APP23 mice and mice expressing mutant Cu/Zn-superoxide dismutase (SOD1), respectively. Exposure for 16 months did not aggravate learning deficit of APP23 mice. Likewise, disease onset and survival of SOD1G85R or SOD1G93A mice were not altered upon LF-MF exposure for ten or eight months, respectively. These results and an extended biochemical analysis of protein aggregation, glial activation and levels of toxic protein species suggests that LF-MF do not affect cellular processes involved in the pathogenesis of AD or ALS.

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“…Despite of intensive investigations the mechanism how aggregates would result in toxicity has remained unclear. It has been suggested that soluble forms of mutSOD1 initiate the disease (Zetterström et al, 2007; Karch et al, 2009) and are, in fact, more toxic than insoluble aggregates (Zetterström et al, 2007; Brotherton et al, 2012; Weichert et al, 2014). Thus, the key appears to involve misfolding and the localization in the mitochondria rather than aggregate formation.…”

Section: Aberrant Mitochondrial Import and Activity Control Of Sod1 Imentioning

confidence: 99%

“…Both Furukawa and Wang also confirmed the existence of heterodimers in vivo , suggesting that formation of heterodimers may be physiologically relevant in FALS patients as well. It has been proposed that the heterodimers comprise a pool of more soluble and more toxic SOD1 whereas homodimers form less toxic aggregates (Weichert et al, 2014). Furthermore, it was demonstrated that wtSOD1 actually reduces aggregate formation of mutSOD1 in cell culture (Witan et al, 2009).…”

Section: Aberrant Mitochondrial Import and Activity Control Of Sod1 Imentioning

confidence: 99%

Mechanisms of mutant SOD1 induced mitochondrial toxicity in amyotrophic lateral sclerosis

Vehviläinen

Koistinaho

Goldsteins

2014

Front. Cell. Neurosci.

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In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction is recognized as one of the key elements contributing to the pathology. Mitochondria are the major source of intracellular reactive oxygen species (ROS). Increased production of ROS as well as oxidative damage of proteins and lipids have been demonstrated in many models of ALS. Moreover, these changes were also observed in tissues of ALS patients indicative of important role for oxidative stress in the disease pathology. However, the origin of oxidative stress in ALS has remained unclear. ALS linked mutant Cu/Zn-superoxide dismutase 1 (SOD1) has been shown to significantly associate with mitochondria, especially in the spinal cord. In animal models, increased recruitment of mutant SOD1 (mutSOD1) to mitochondria appears already before the disease onset, suggestive of causative role for the manifestation of pathology. Recently, substantial in vitro and in vivo evidence has accumulated demonstrating that localization of mutSOD1 to the mitochondrial intermembrane space (IMS) inevitably leads to impairment of mitochondrial functions. However, the exact mechanisms of the selectivity and toxicity have remained obscure. Here we discuss the current knowledge on the role of mutSOD1 in mitochondrial dysfunction in ALS from the novel perspective emphasizing the misregulation of dismutase activity in IMS as a major mechanism for the toxicity.

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Wild-type Cu/Zn superoxide dismutase stabilizes mutant variants by heterodimerization

Cited by 16 publications

References 61 publications

SOD1 misplacing and mitochondrial dysfunction in amyotrophic lateral sclerosis pathogenesis

SOD1 misplacing and mitochondrial dysfunction in amyotrophic lateral sclerosis pathogenesis

Low-frequency magnetic fields do not aggravate disease in mouse models of Alzheimer's disease and amyotrophic lateral sclerosis

Mechanisms of mutant SOD1 induced mitochondrial toxicity in amyotrophic lateral sclerosis

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