Clioquinol Improves Cognitive, Motor Function, and Microanatomy of the Alpha-Synuclein hA53T Transgenic Mice.
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 Florey Institute of Neuroscience and Mental Health, The University of Melbourne , Parkville, Victoria 3052, Australia.
David I
DI
Finkelstein
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne , Parkville, Victoria 3052, Australia.|Elemental Bio-imaging Facility, University of Technology Sydney , Broadway, New South Wales 2007, Australia.|Senator Frank R. Lautenberg Environmental Science Laboratory, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Dominic J
DJ
Hare
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne , Parkville, Victoria 3052, Australia.
Jessica L
JL
Billings
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne , Parkville, Victoria 3052, Australia.
Amelia
A
Sedjahtera
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne , Parkville, Victoria 3052, Australia.
Milawaty
M
Nurjono
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne , Parkville, Victoria 3052, Australia.|Department of Physiology and Pharmacology, Karolinska Institut , Stockholm SE-171 77, Sweden.
Elisa
E
Arthofer
School of Medicine, Dentistry and Health Sciences, The University of Melbourne , Parkville, Victoria 3052, Australia.
Sonia
S
George
School of Medicine, Dentistry and Health Sciences, The University of Melbourne , Parkville, Victoria 3052, Australia.
Janetta G
JG
Culvenor
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne , Parkville, Victoria 3052, Australia.
Ashley I
AI
Bush
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne , Parkville, Victoria 3052, Australia.
Paul A
PA
Adlard
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D007464:Clioquinol / Q000494:pharmacology / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects; D016622:Silver Staining; D065853:Spatial Learning / Q000187:drug effects; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
D051844:alpha-Synuclein; D007464:Clioquinol
A53T; Clioquinol; Parkinson’s disease; alpha-synuclein