Clioquinol Improves Cognitive, Motor Function, and Microanatomy of the Alpha-Synuclein hA53T Transgenic Mice

Abstract

The abnormal accumulation of alpha-synuclein (α-syn) has been linked to a number of neurodegenerative disorders, the most noteworthy of which is Parkinson's disease. Alpha-synuclein itself is not toxic and fulfills various physiological roles in the central nervous system. However, specific types of aggregates have been shown to be toxic, and metals have been linked to the assembly of these toxic aggregates. In this paper, we have characterized a transgenic mouse that overexpresses the A53T mutation of human α-syn, specifically assessing cognition, motor performance, and subtle anatomical markers that have all been observed in synucleinopathies in humans. We hypothesized that treatment with the moderate-affinity metal chelator, clioquinol (CQ), would reduce the interaction between metals and α-syn to subsequently improve the phenotype of the A53T animal model. We showed that CQ prevents an iron-synuclein interaction, the formation of urea-soluble α-syn aggregates, α-syn-related substantia nigra pars compacta cell loss, reduction in dendritic spine density of hippocampal and caudate putamen medium spiny neurons, and the decline in motor and cognitive function. In conclusion, our data suggests that CQ is capable of mitigating the pathological metal/α-syn interactions, suggesting that the modulation of metal ions warrants further study as a therapeutic approach for the synucleinopathies.

The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease

“…The hA53T mutant α- synuclein transgenic mouse has a subtle disease phenotype [12, 14, 31, 35, 72]. At 8 months of age, the hA53T mice exhibit decreased locomotion in the open field test compared with wild type animals, and hindlimb clasping behavior (Additional file 1: Figure S6), indicative of striatal damage.…”

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

“…Genetic mutation of Cu-ATPase (ATP7A) has been found to cause diseases of copper deficiency in the brain and the specific mutation of ATP7B results in diseases of copper accumulation (Lutsenko et al, 2007; Choi and Zheng, 2009; Davies et al, 2016). Recent work has examined copper chelation as a means to reduce free-radical damage, with clioquinol (a metal chelator) shown to reduce aggregation of beta-amyloid and alpha-synuclein in transgenic mice (Cherny et al, 2001; Adlard et al, 2008; Finkelstein et al, 2016). Metallothioneins (MT), contribute to copper regulation and may also act as ROS absorbers (Carter et al, 1984; Otsuka, 2004; Lutsenko et al, 2007).…”

Transcriptomic profiling of purified patient-derived dopamine neurons identifies convergent perturbations and therapeutics for Parkinson’s disease

“…It was shown in 2003 to prevent dopaminergic cell death in the MPTP toxin mouse model of Parkinson’s, most likely through a reduction in reactive iron (35). More recently, clioquinol has been shown to rescue cognitive and motor function, and dopamine neuron loss in α-synuclein hA53T transgenic mice (34) and in microtubule associated protein tau knockout ( Mapt-/- ) mice (32). Clioquinol has also shown promise in the treatment of mouse models of Alzheimer’s disease (AD) (40) and has been used in a small Phase 2 trial for AD in which it was well tolerated and appeared to reduce cognitive decline (41).…”