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Neurotoxicity of Metals

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Attention for Chapter 6: Manganese and the Insulin-IGF Signaling Network in Huntington's Disease and Other Neurodegenerative Disorders.
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Chapter title
Manganese and the Insulin-IGF Signaling Network in Huntington's Disease and Other Neurodegenerative Disorders.
Chapter number 6
Book title
Neurotoxicity of Metals
Published in
Advances in neurobiology, January 2017
DOI 10.1007/978-3-319-60189-2_6
Pubmed ID
Book ISBNs
978-3-31-960188-5, 978-3-31-960189-2

Bryan, Miles R, Bowman, Aaron B, Miles R. Bryan, Aaron B. Bowman, Bryan, Miles R., Bowman, Aaron B.


Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting in motor impairment and death in patients. Recently, several studies have demonstrated insulin or insulin-like growth factor (IGF) treatment in models of HD, resulting in potent amelioration of HD phenotypes via modulation of the PI3K/AKT/mTOR pathways. Administration of IGF and insulin can rescue microtubule transport, metabolic function, and autophagy defects, resulting in clearance of Huntingtin (HTT) aggregates, restoration of mitochondrial function, amelioration of motor abnormalities, and enhanced survival. Manganese (Mn) is an essential metal to all biological systems but, in excess, can be toxic. Interestingly, several studies have revealed the insulin-mimetic effects of Mn-demonstrating Mn can activate several of the same metabolic kinases and increase peripheral and neuronal insulin and IGF-1 levels in rodent models. Separate studies have shown mouse and human striatal neuroprogenitor cell (NPC) models exhibit a deficit in cellular Mn uptake, indicative of a Mn deficiency. Furthermore, evidence from the literature reveals a striking overlap between cellular consequences of Mn deficiency (i.e., impaired function of Mn-dependent enzymes) and known HD endophenotypes including excitotoxicity, increased reactive oxygen species (ROS) accumulation, and decreased mitochondrial function. Here we review published evidence supporting a hypothesis that (1) the potent effect of IGF or insulin treatment on HD models, (2) the insulin-mimetic effects of Mn, and (3) the newly discovered Mn-dependent perturbations in HD may all be functionally related. Together, this review will present the intriguing possibility that intricate regulatory cross-talk exists between Mn biology and/or toxicology and the insulin/IGF signaling pathways which may be deeply connected to HD pathology and, perhaps, other neurodegenerative diseases (NDDs) and other neuropathological conditions.

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Geographical breakdown

Country Count As %
Unknown 52 100%

Demographic breakdown

Readers by professional status Count As %
Student > Bachelor 9 17%
Researcher 8 15%
Student > Ph. D. Student 7 13%
Other 6 12%
Student > Master 3 6%
Other 6 12%
Unknown 13 25%
Readers by discipline Count As %
Medicine and Dentistry 10 19%
Biochemistry, Genetics and Molecular Biology 9 17%
Neuroscience 6 12%
Pharmacology, Toxicology and Pharmaceutical Science 5 10%
Agricultural and Biological Sciences 2 4%
Other 2 4%
Unknown 18 35%