Abstract
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.
Highlights
Imbalanced copper (Cu) homeostasis has been associated with the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and familial amyotrophic lateral sclerosis (ALS) [1,2,3]
The uptake, efflux and distribution of Cu across cell membranes are mediated by membrane-integrated Cu transporters, including Cu transporter 1 (CTR1), divalent metal transporters (DMTs) and P-type ATPases, ATP7A and ATP7B, respectively
The two cuproenzymes that are largely expressed in the nervous system and rely on ATP7A Cu delivery for activation are the peptidylα-monooxygenase (PAM) and dopamine-β-hydroxylase (DBH), both belong to the monooxygenase family and require two Cu atoms in each monomer to be functional
Summary
Imbalanced copper (Cu) homeostasis has been associated with the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and familial amyotrophic lateral sclerosis (ALS) [1,2,3]. The uptake, efflux and distribution of Cu across cell membranes are mediated by membrane-integrated Cu transporters, including Cu transporter 1 (CTR1), divalent metal transporters (DMTs) and P-type ATPases, ATP7A and ATP7B, respectively These transporters further distribute Cu to different organelles via their corresponding chaperones in a Cu-dependent manner. Dysregulation of membrane trafficking could result in misplacement of Cu transporters, imbalance between Cu uptake and exclusion and immaturity of functional cuproproteins, perturbing Cu distribution [7,8,9,10]. These findings highlight the importance of membrane trafficking in modulating Cu homeostasis. The molecular picture of interplaying pathways between membrane trafficking machinery and Cu homeostasis could help understand Cu transporters’ physiological configurations, signalling and behaviour dynamics in maintaining neuronal Cu balance
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