Association of cerebral spinal fluid copper imbalance in amyotrophic lateral sclerosis

Chen, Qiao Yi; Wu, Peng; Wen, Ting; Qin, Xing; Jia, Rui; Jin, Jiaoting; Hu, Fangfang; Xie, Xiaoge; Dang, Jingxia

doi:10.3389/fnagi.2022.970711

Cited by 8 publications

(1 citation statement)

References 93 publications

(121 reference statements)

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“…It is therefore likely that failure of the chaperone system itself can simultaneously cause functional deficiency and toxic overload. In ALS there is an imbalance of copper, with a mix of both copper deficiency and overload which can be explained by the mis-partitioning of copper stores, with a loss of cuproenzyme function and increased amounts of copper-bound aggregates, which will be discussed later ( Gil-Bea et al, 2017 ; Barros et al, 2018 ; Chen Q. Y. et al, 2022 ). While copper is a well-known inducer of cell death, until recently the exact underlying mechanism in mammalian cells was not fully elucidated.…”

Section: Copper and Cell Death: How Does Copper Kill?mentioning

confidence: 99%

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

Min,

Sarlus,

Harris

2024

Front. Mol. Neurosci.

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The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.

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Section: Copper and Cell Death: How Does Copper Kill?mentioning

confidence: 99%