Abstract
BackgroundAberrant biometal metabolism is a key feature of neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Metal modulating compounds are promising therapeutics for neurodegeneration, but their mechanism of action remains poorly understood. Neuronal ceroid lipofuscinoses (NCLs), caused by mutations in CLN genes, are fatal childhood neurodegenerative lysosomal storage diseases without a cure. We previously showed biometal accumulation in ovine and murine models of the CLN6 variant NCL, but the mechanism is unknown. This study extended the concept that alteration of biometal functions is involved in pathology in these disorders, and investigated molecular mechanisms underlying impaired biometal trafficking in CLN6 disease.ResultsWe observed significant region-specific biometal accumulation and deregulation of metal trafficking pathways prior to disease onset in CLN6 affected sheep. Substantial progressive loss of the ER/Golgi-resident Zn transporter, Zip7, which colocalized with the disease-associated protein, CLN6, may contribute to the subcellular deregulation of biometal homeostasis in NCLs. Importantly, the metal-complex, ZnII(atsm), induced Zip7 upregulation, promoted Zn redistribution and restored Zn-dependent functions in primary mouse Cln6 deficient neurons and astrocytes.ConclusionsThis study demonstrates the central role of the metal transporter, Zip7, in the aberrant biometal metabolism of CLN6 variants of NCL and further highlights the key contribution of deregulated biometal trafficking to the pathology of neurodegenerative diseases. Importantly, our results suggest that ZnII(atsm) may be a candidate for therapeutic trials for NCLs.
Highlights
Biometals including Zn and Cu are immensely important for brain function
Impaired lysosomal function and neurodegenerationassociated proteinopathy in Neuronal ceroid lipofuscinosis (NCL) Lysosomal dysfunction, prior to the onset of clinical signs in CLN6 affected Merino sheep, which occurs at 8–12 months [17], was demonstrated by reduced cathepsin D activity from 3 months of age (Figure 1A)
These data indicate that disturbances to biometal homeostasis may precede detectable clinical signs in CLN6 disease
Summary
Biometals including Zn and Cu are immensely important for brain function. When homeostatic control fails in aging or disease, biometal mislocalization or altered homeostasis can drive pathological changes as observed in patients suffering from neurodegenerative diseases [1], as the brain is especially vulnerable to metal-induced oxidativeNeuronal ceroid lipofuscinoses (NCLs), commonly known as Batten diseases, are a genetically heterogeneous group of lysosomal storage diseases (LSDs) [3], characterized by storage of lipofuscin material in lysosome-derived fluorescent storage bodies [4,5] and neuronal demise leading to progressive loss of vision, motor dysfunction and premature death [6]. We previously demonstrated region-specific alterations to biometal homeostasis in ovine CLN6 disease that correlated with the development of neurodegeneration [14]. We show that altered biometal trafficking pathways involve loss of ER-co-localized transmembrane proteins, CLN6 and the metal transporter Zip, triggering subcellular metal accumulation in presymptomatic CLN6 disease. Correction of impaired metal-dependent functions in Cln cells is achieved via up-regulation of Zip by a cell permeable metal complex, ZnII(atsm). These studies demonstrate the potential of biometal modulation for the development of therapeutics for CLN6 disease. This study extended the concept that alteration of biometal functions is involved in pathology in these disorders, and investigated molecular mechanisms underlying impaired biometal trafficking in CLN6 disease
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