The Pivotal Role of Copper in Neurodegeneration: A New Strategy for the Therapy of Neurodegenerative Disorders

Abstract

Copper is an essential trace element for the human body since it is a cofactor of several enzymes and proteins and plays a pivotal role in several biological functions (e.g., respiration, protection from oxidative damage, iron metabolism, etc.), also including the central nervous system development and functioning (e.g., synthesis of neurotransmitters, myelination, activation of neuropeptides, etc.). Therefore, copper dysmetabolism is associated with different toxic effects, mainly represented by oxidative stress, and it has been reported in many neurodegenerative disorders, such as Wilson's disease, Menkes disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This paper shows a detailed report of how copper is involved in the pathophysiology of these diseases. Moreover, a hint on novel therapeutic approaches based on restoring copper homeostasis through metal chelators will be pointed out.

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

“…Many mechanisms have been considered and reviewed for the damage induced by Cu [44], Fe [49,[64][65][66], Mn [67] and Zn [49] under PD conditions; in several cases, oxidative damage, metal dyshomeostasis and α-syn aggregation have been demonstrated to be strictly related to each other.…”

Lead Exposure Induced Copper Clearance Disorder of Blood-CSF Barrier

“…However, excessive copper may cause adverse systemic effects. It has been demonstrated that the level of copper in brain have a subtle relationship with the progress of some neurodegenerative diseases [39][40][41]. It is suggested that lead could indirectly alter copper metabolism that manifest as lead neurotoxicity.…”

Is copper a new target to counteract the progression of chronic diseases?

“…44 To date, the molecular mechanisms at the basis of the pathogenic effects of ATP7A inactivation are yet to be clarified, even if it is known that this condition leads to altered Cu concentrations in cytosol, nuclei and mitochondria. 45 Although most mutations in the ATP7A gene cause Menkes' disease, some missense mutations induce a weaker disease called Occipital Horn Syndrome. 46,47 Patients with Occipital Horn Syndrome suffer from connective tissue abnormalities as with Menkes' disease patients, but do not usually present neurological symptoms and have a considerably longer average lifespan.…”

“…At the same time, the incorporation of Cu into ceruloplasmin is impaired, thus elevated levels of free Cu are released into the bloodstream exerting extrahepatic Cu toxicity. 45 Interestingly enough, polymorphism in the ATP7B gene has also been associated with an increased risk of Alzheimer's disease (AD) and may be useful to stratify specific metabolic subtypes of AD. 48 AD is a late-onset multifactorial disease and is related to multiple risk factors.…”

“…69 SOD1 is a major Cu-binding protein and regulates Cu homeostasis in cells; therefore, toxicity of mutant SOD1 could arise from the disruption of Cu homeostasis. 45 Interestingly, increased levels of Cu have been evidenced in the ventral areas of the spinal cords of sporadic ASL patients, as well as other metals (lead and zinc), but mutations in the SOD1 gene have not been highlighted in those cases. To note, even over-expression of SOD1 alone, still able to bind Cu, can function as an efficient trigger for increasing Cu spinal levels; this effect is probably due to the high Cu affinity of this enzyme.…”