Manganese and the Insulin-IGF Signaling Network in Huntington’s Disease and Other Neurodegenerative Disorders

Abstract

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.

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation

“…Manganese is a naturally occurring trace element that is essential for human development and brain function. Excessive manganese is neurotoxic and has been linked to developmental disorders and neurodegenerative disorders associated with basal ganglia dysfunction, such as Parkinson's disease and Huntington's disease [206][207][208] . Moreover, the relevance of manganese for the regulation of brain functions has been further emphasized by the discovery of loss-of-function mutations in genes related to its transport, which lead to neurotoxicity [209] .…”

Brain manganese and the balance between essential roles and neurotoxicity

“…Together taken these studies point to a connection between Mn and the regulation of IGF-1/insulin level. The reader is referred to recent reviews that discuss changes in the neuronal urea cycle, insulin signaling and the cellular process of autophagy that are linked to Mn health and dysfunction associated with changes in brain Mn levels in depth (105,132,(208)(209)(210)(211)(212)(213).…”

Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment

“…The implication of IR and IR‐related indirect mechanisms was documented during various challenges in adulthood that include aging, neurodegeneration, stress, and exposure to toxins such as alcohol, and are related to the roles of IR in the neuroprotection …”

“…Fundamental roles of the IR‐mediated signaling in brain development are reflected by numerous associations reported between its deficiency and neurodevelopmental disorders, such as autism and schizophrenia, as well as cancer, including cerebellar neoplasms and other syndromes . Altered neuroprotective functions of IR are ascribed to the contribution of IR‐related signaling to the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, and Parkinson's disorder; major depression; and neurotoxicity …”