The M1311V variant of ATP7A is associated with impaired trafficking and copper homeostasis in models of motor neuron disease

Bakkar, Nadine; Starr, Alexander; Rabichow, Benjamin E.; Lorenzini, Ileana; McEachin, Zachary T.; Kraft, Robert A.; Chaung, Matthew; Macklin-Isquierdo, Sam; Wingfield, Taylor; Carhart, Briggs S; Zahler, Nathan H.; Chang, Wei-Feng; Bassell, Gary J.; Bétourné, Alexandre; Boulis, Nicholas M.; Alworth, Samuel V.; Ichida, Justin K.; August, Paul R.; Zarnescu, Daniela C.; Sattler, Rita; Bowser, Robert

doi:10.1016/j.nbd.2020.105228

Cited by 19 publications

(9 citation statements)

References 64 publications

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“…Increases in Cu concentration stimulate the trafficking of ATP7A/B proteins to the recycling vesicles near the PM, where ATP7A/B efflux Cu to ensure proper intracellular Cu fluxes and avoid potentially toxic Cu accumulation. Mutations in ATP7A/B or the membrane trafficking regulators could affect ATP7A/B's exit from or subsequent retrieval to the Golgi apparatus [115][116][117][118][119]. This disturbed trafficking, in turn, disrupts the homeostatic Cu balance, resulting in Cu deficiency (MD) or Cu overload (WD).…”

Section: Golgi Apparatusmentioning

confidence: 99%

Crossroads between membrane trafficking machinery and copper homeostasis in the nerve system

et al. 2021

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Imbalanced copper homeostasis and perturbation of membrane trafficking are two common symptoms that have been associated with the pathogenesis of neurodegenerative and neurodevelopmental diseases. Accumulating evidence from biophysical, cellular and in vivo studies suggest that membrane trafficking orchestrates both copper homeostasis and neural functions—however, a systematic review of how copper homeostasis and membrane trafficking interplays in neurons remains lacking. Here, we summarize current knowledge of the general trafficking itineraries for copper transporters and highlight several critical membrane trafficking regulators in maintaining copper homeostasis. We discuss how membrane trafficking regulators may alter copper transporter distribution in different membrane compartments to regulate intracellular copper homeostasis. Using Parkinson's disease and MEDNIK as examples, we further elaborate how misregulated trafficking regulators may interplay parallelly or synergistically with copper dyshomeostasis in devastating pathogenesis in neurodegenerative diseases. Finally, we explore multiple unsolved questions and highlight the existing challenges to understand how copper homeostasis is modulated through membrane trafficking.

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Section: Golgi Apparatusmentioning

confidence: 99%

Crossroads between membrane trafficking machinery and copper homeostasis in the nerve system

et al. 2021

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“…Recently, a novel mutation in the P domain of ATP7A (ATP7A M1311V ) was associated with impaired motor neuron function and neurodegeneration in a patient with man‐in‐barrel syndrome with slow‐progressing ALS 503 . The mutation was shown to reduce ATP7A localization in the TGN, resulting in oxidative stress, expression of cell‐damage markers, and reduced dendritic complexity and firing of action potentials in iPSCs differentiated into motor neurons 503,504 . This phenotype was rescued by CRISPR/Cas9 correction of the mutant ATPase 503 and has been postulated as a contributor to ALS progression 504 …”

Section: Diseases Of the Central Nervous System Associated With Cu Dy...mentioning

confidence: 99%

“…503 The mutation was shown to reduce ATP7A localization in the TGN, resulting in oxidative stress, expression of cell-damage markers, and reduced dendritic complexity and firing of action potentials in iPSCs differentiated into motor neurons. 503,504 This phenotype was rescued by CRISPR/Cas9 correction of the mutant ATPase 503 and has been postulated as a contributor to ALS progression. 504 The CuATSM complex selectively releases Cu into cells with impaired mitochondrial electron transport.…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

“…503,504 This phenotype was rescued by CRISPR/Cas9 correction of the mutant ATPase 503 and has been postulated as a contributor to ALS progression. 504 The CuATSM complex selectively releases Cu into cells with impaired mitochondrial electron transport. 505,506 Apo-ATSM has a high affinity for Cu 2+ and showed no preventive effect against ALS in SOD1-mutant murine models.…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

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The molecular and cellular basis of copper dysregulation and its relationship with human pathologies

et al. 2021

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Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu + -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in K E Y W O R D S cancer, copper, copper-dependent diseases, cuproproteins, Menkes disease, mitochondrial myopathies, Wilson disease

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“…A study on human-induced motor neurons (iMNs) revealed that apilimod increases the iMNs survival of C9orf72 patients (Shi et al, 2018). Similarly, apilimod shows a significant activity in the reduction of the neuronal death in MAPT mutated cells (Bowles et al, 2021) and in ATP7A iMNs (Bakkar et al, 2021).…”

Section: Lam-002amentioning

confidence: 99%

C9orf72-Related Neurodegenerative Diseases: From Clinical Diagnosis to Therapeutic Strategies

Zampatti

Peconi

Campopiano

et al. 2022

Front. Aging Neurosci.

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Hexanucleotide expansion in C9orf72 has been related to several phenotypes to date, complicating the clinical recognition of these neurodegenerative disorders. An early diagnosis can improve the management of patients, promoting early administration of therapeutic supportive strategies. Here, we report known clinical presentations of C9orf72-related neurodegenerative disorders, pointing out suggestive phenotypes that can benefit the genetic characterization of patients. Considering the high variability of C9orf72-related disorder, frequent and rare manifestations are described, with detailed clinical, instrumental evaluation, and supportive therapeutical approaches. Furthermore, to improve the understanding of molecular pathways of the disease and potential therapeutical targets, a detailed description of the cellular mechanisms related to the pathological effect of C9orf72 is reported. New promising therapeutical strategies and ongoing studies are reported highlighting their molecular role in cellular pathological pathways of C9orf72. These therapeutic approaches are particularly promising because they seem to stop the disease before neuronal damage. The knowledge of clinical and molecular features of C9orf72-related neurodegenerative disorders improves the therapeutical application of known strategies and will lay the basis for the development of new potential therapies.

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The M1311V variant of ATP7A is associated with impaired trafficking and copper homeostasis in models of motor neuron disease

Cited by 19 publications

References 64 publications

Crossroads between membrane trafficking machinery and copper homeostasis in the nerve system

Crossroads between membrane trafficking machinery and copper homeostasis in the nerve system

The molecular and cellular basis of copper dysregulation and its relationship with human pathologies

C9orf72-Related Neurodegenerative Diseases: From Clinical Diagnosis to Therapeutic Strategies

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