Copper Metabolism and Cuproptosis:Molecular Mechanisms and Therapeutic Perspectives in Neurodegenerative Diseases

Copper is an essential trace element,and plays a vital role in numerous physiological processes within the human body.During normal metabolism,the human body maintains copper homeostasis.Copper deficiency or excess can adversely affect cellular function.Therefore,copper homeostasis is stringently regulated.Recent studies suggest that copper can trigger a specific form of cell death,namely,cuproptosis,which is triggered by excessive levels of intracellular copper.Cuproptosis induces the aggregation of mitochondrial lipoylated proteins,and the loss of iron-sulfur cluster proteins.In neurodegenerative diseases,the pathogenesis and progression of neurological disorders are linked to copper homeostasis.This review summarizes the advances in copper homeostasis and cuproptosis in the nervous system and neurodegenerative diseases.This offers research perspectives that provide new insights into the targeted treatment of neurodegenerative diseases based on cuproptosis.

Wilson disease-the impact of hyperimmunity on disease activity:A case report

BACKGROUND In Wilson disease lack of biliary copper excretion causes hepatocellular injury by accumulation of free toxic copper.Its overspill to serum accounts for neuronal damage as second common manifestation.Therapy with copper chelators or zinc targets the removal of this free copper.However,in some patients liver disease persists for unknown reason despite normalized free copper.The discovery of a hyperimmunity as a contributing pathogenetic factor was discovered in this case report with implication also for other liver diseases.CASE SUMMARY A 9-year-old girl was diagnosed in August 2009 by family screening of having asymptomatic Wilson disease with elevated transaminases.Already at time of diagnosis antinuclear antibodies(ANA)were elevated without hyperimmunoglobulinemia(immunoglobulin G,IgG).After one year of therapy with Dpenicillamine transaminases normalized together with free serum copper.Under continuous therapy with copper chelators free copper remained normal until today,whereas transaminases raised to alanine aminotransferase values of 571 U/L in December 2019.For hyperimmunity a tentative steroid course on top of Dpenicillamine improved transaminases.Thus,hyperimmunity may have impact on liver inflammation after control of the metabolic disturbance.A retrospective cohort study confirmed the common association of elevated transaminases with ANA,but no IgG elevation.CONCLUSION This hyperimmune-triggered condition may represent a new entity which per se or on top of other liver diseases induces liver inflammation responsive to steroids.

Novel ATP7B gene mutations in Chinese Han patients with hepatolenticular degeneration

BACKGROUND： ATP7B gene exon 8 Arg778Leu and exon 12 Arg952Lys are gene mutation hot spots in Chinese Han patients with hepatolenticular degeneration, or Wilson＇s disease （WD）. However, the gene fragments are too short for detection and the mutation detection rate remains low. OBJECTIVE： To analyze DNA sequences of ATP7B gene exon 8-exon 9 and exon 10-exon 12 sections. DESIGN, TIME AND SE＇I-rlNG： A concurrent, non-randomized, controlled, genetic polymorphism study was performed at the Anhui Medical Genetics Center, Anhui, China from March to July in 2009. PARTICIPANTS： Fifty patients, who were admitted to the Department of Neurology at the First Affiliated Hospital of Anhui Traditional Chinese Medical College between March and July in 2009, were diagnosed with WD. The WD group comprised 32 males and 18 females, with an average age of （18.8 ± 8.3） years. WD was confirmed by clinical observation, as well as physical, imaging, and biochemical examinations, including testing for serum copper, ceruloplasmin, and copper oxidase. The control group comprised 20 normal subjects, who underwent physical examination at the First Affiliated Hospital of Anhui Traditional Chinese Medical College, and included 13 males and 7 females, with an average age of （27.9 ± 2.4） years. All subjects were Chinese Han population. METHODS： Genomic DNA was extracted from 50 WD patients and 20 normal controls. Polymerase chain reaction amplification of ATP7B gene exon 8-exon 9 （about 1 100 bp） and exon 10-exon 12 （about 850 bp） segments was performed. DNA exon-intron amplification products from all subjects were processed through direct bidirectional sequencing, and sequencing results were analyzed. MAIN OUTCOME MEASURES： Sequence changes of ATPTB gene exon 8-exon 9 and exon 10-exon 12 segments. RESULTS： In the 50 included WD patients, ATP7B gene intron 8 nt53592A → G with nt53671G→ A homozygous mutation was detected between exon 8-exon 9 in seven cases; exon 8 Arg778Leu mutations with Leu770Leu synonymous mutation was detected in four cases; exert 11 Gly790Arg heterozygous missense mutation between exon 10-exon 12 was found in four cases; exon 12 Arg952Lys heterozygous missense mutation was seen in 11 cases; and two additional cases were associated with exon 1211e929Val polymorphism. CONCLUSION： ATP7B gene intron 8 mutation is a possible pathogenic mutation that is associated with WD pathogenesis. The exon 11 mutation rate accounts for 8% of all WD patients, and the very few previously reported cases deserve further study.

The mechanism of copper homeostasis and its role in disease

Copper(Cuprum)is an essential trace metal indispensable for the function of numerous enzymatic molecules implicated in cellular metabolism.Emerging evidence has demonstrated the role of copper in angiogenesis and cellular signaling.Moreover,raised copper levels have been detected in hepatocellular carcinoma and other cancers.An inherited or acquired copper imbalance,including inadequately low or excessively high copper levels,as well as inappropriate copper distribution in the body,is implicated in a number of diseases.In addition,a recent groundbreaking study identified a copperinduced type of programmed cell death named cuprotosis,the mechanism of which greatly deferred from that of other known cell death modes.The first part provides an overview of the regulation of copper homeostasis and discusses the underlying mechanisms of cuprotosis.In the second part,the authors focus on the functions of copper in liver diseases and other metabolic disorders,before discussing how this knowledge could contribute to the development of effective targets to treat such diseases.

Reversible lesions in the brain parenchyma in Wilson's disease confirmed by magnetic resonance imaging:earlier administration of chelating therapy can reduce the damage to the brain

The aim of this study was to evaluate the resolution of brain lesions in patients with Wilson’s disease during the long-term chelating therapy using magnetic resonance imaging and a possible signiifcance of the time latency between the initial symptoms of the disease and the introduction of this therapy. Initial magnetic resonance examination was performed in 37 patients with proven neurological form of Wilson’s disease with cerebellar, parkinsonian and dystonic presentation. Magnetic resonance reexamination was done 5.7 ± 1.3 years later in 14 patients. Patients were divided into： group A, where chelating therapy was initiated 〈 24 months from the ifrst symp-toms and group B, where the therapy started≥ 24 months after the initial symptoms. Symmetry of the lesions was seen in 100% of patients. There was a signiifcant difference between groups A and B regarding complete resolution of brain stem and putaminal lesions （P= 0.005 andP=0.024, respectively）. If the correct diagnosis and adequate treatment are not established less than 24 months after onset of the symptoms, irreversible lesions in the brain parenchyma could be ex-pected. Signal abnormalities on magnetic resonance imaging might therefore, at least in the early stages, represent reversible myelinolisis or cytotoxic edema associated with copper toxicity.