The Zinc Ionophore Clioquinol Reduces Parkinson’s Disease Patient-Derived Brain Extracts-Induced Neurodegeneration

Abstract

Parkinson's Disease (PD) is characterized by intracellular α-synuclein-rich protein aggregates, named Lewy Bodies (LB), and by the progressive loss of dopaminergic neurons in the substantia nigra. Several heavy metals, including zinc (Zn), have been suggested to play a role in PD progression, although the exact role of Zn in neurodegeneration remains to be fully elucidated. To address this gap, we investigated the effects of Zn modulation on the progression of degeneration in mice injected with PD patient-derived LB-extracts carrying toxic α-synuclein aggregates. Zn modulation was achieved using either a clioquinolenriched diet, a Zn ionophore that redistributes cellular Zn, or a Zn-enriched diet that increases Zn levels. Clioquinol treatment signi cantly prevented dopaminergic neurodegeneration and reduced α-synucleinassociated pathology in LB-injected mice, while no differences were observed with Zn supplementation. Biochemical analyses further demonstrate that the expression levels of vesicle-speci c Zn transporter ZnT3 in the striatum of LB-injected mice treated with clioquinol were decreased, suggesting an intracellular redistribution of Zn. Additionally, we found that clioquinol modulates the autophagylysosomal pathway by enhancing lysosomal redistribution within the neuronal compartments.Collectively, we found that in vivo pharmacological chelation of Zn, by dampening Zn-mediated cytotoxicity, can result in an overall attenuation of PD-linked lysosomal alterations and dopaminergic neurodegeneration. The results support zinc chelation as a disease-modifying strategy for treating PD.

A distinct signalling circuit upregulates cytotoxic ROS production in a cellular model of Parkinson’s disease: key roles for TRPM2, Zn2+and complex III

“…It is likely that in other ROS-driven diseases, where Ca 2+ is implicated, Zn 2+ plays a downstream role in generating pathogenic ROS. The beneficial effects of Zn 2+ chelators in some experimental disease models including neurodegenerative 47, 49, 50 and metabolic diseases 51 lend some support to this plausibility.…”

“…Fourth, zinc transporters are upregulated in the brains of PD patients 45 . Fifth, Zn 2+ chelators protect mice against neurodegeneration in substantia nigra in in vivo models 47 . Finally, mutations in the PD associated PARK9 gene disrupt Zn 2+ as well as ROS homeostasis 48 .…”

Genetic Targets and Applications of Iron Chelators for Neurodegeneration with Brain Iron Accumulation

“…VK-28 and M30 are derivatives of 8-hydroxyquinolines, a family of compounds that can form complexes with divalent metal cations such as iron . Clioquinol is a member of this family that is primarily used as an antibiotic and to treat pulmonary fibrosis, but it has also been used in cases of AD/PD with success. ,− These studies have made clioquinol an attractive compound for neurodegeneration treatments, but clioquinol has also been proven to cause cytotoxicity in astrocyte-derived KT-5 cells by depleting ATP levels and increasing ROS in the cells . Though clioquinol may not be a viable therapy for NBIA, related compounds such as VK-28 and M30 have the same chelation properties without the cytotoxicity of their relative, so their application toward these diseases has potential.…”

Targeting the pathogenesis and boosting the therapeutic efficacy of Parkinson's disease by advanced nanoparticles

“…As the second most abundant transition metal in the brain, zinc ions (Zn 2+ ) can directly inhibit the activity of tyrosine hydroxylase and antagonize the binding of Fe 2+ ions, thus negatively regulate dopamine synthesis 146 . Chelation of zinc ions can alleviate PD‐associated lysosomal alterations and dopaminergic neurodegeneration by inhibiting zinc‐mediated cytotoxicity 147 . The disorder of manganese metabolism is also associated with PD, because manganese can affect neurotransmitter synthesis, and release, particularly in the basal ganglia 148,149 .…”

“…146 Chelation of zinc ions can alleviate PD-associated lysosomal alterations and dopaminergic neurodegeneration by inhibiting zincmediated cytotoxicity. 147 The disorder of manganese metabolism is also associated with PD, because manganese can affect neurotransmitter synthesis, and release, particularly in the basal ganglia. 148,149 For example, manganese may compete with Ca 2+ influx, increase neurotransmitter release and the rhythmic firing activity in dopaminergic neurons, which may cause their dysfunction.…”