Metal homeostasis disturbances in neurodegenerative disorders, with special emphasis on Creutzfeldt-Jakob disease - Potential pathogenetic mechanism and therapeutic implications.

Abstract

Creutzfeldt-Jakob disease (CJD) is characterized by a rapidly progressive dementia often accompanied by myoclonus and other signs of brain dysfunction, relying on the conversion of the normal cellular form of the prion protein (PrPC) to a misfolded form (PrPSc). The neuropathological changes include spongiform degeneration, neuronal loss, astrogliosis, and deposition of PrPSc. It is still unclear how these pathological changes correlate with the development of CJD symptoms because few patients survive beyond 2years after diagnosis. Inasmuch as the symptoms of CJD overlap some of those observed in Alzheimer's, Parkinson's, and Huntington's diseases, there may be some underlying pathologic mechanisms associated with CJD that may contribute to the symptoms of non-prion neurodegenerative diseases as well. Data suggest that imbalance of metals, including copper, zinc, iron, and manganese, induces abnormalities in processing and degradation of prion proteins that are accompanied by self-propagation of PrPSc. These events appear to be responsible for glutamatergic synaptic dysfunctions, neuronal death, and PrPSc aggregation. Given that the prodromal symptoms of CJD such as sleep disturbances and mood disorders are associated with brain stem and limbic system dysfunction, the pathological changes may initially occur in these brain regions, then spread throughout the entire brain. Alterations in cerebrospinal fluid homeostasis, which may be linked to imbalance of these metals, seem to be more important than neuroinflammation in causing the cell death. It is proposed that metal dyshomeostasis could be responsible for the initiation and progression of the pathological changes associated with symptoms of CJD and other neurodegenerative disorders.