Views on neurodegeneration as a basis for neuroprotective strategies

Evidence is presented to demonstrate neurodegenerative processes in Parkinson's disease which are interconnected and may be synergistic in a way that they self-perpetuate progression. Free iron plays a predominant role, because it may be continuously and unlimitedly taken up through a disturbed blood-brain-barrier. Iron's toxic action is at both neuronal and glial sites. Loss of tyrosine hydroxylase protein and activity and fibrillation of alpha-synuclein connected with disturbed proteasomal protein breakdown contribute to cell death, as are changes in neuromelanin concentration and binding affinity, e.g. for iron. The interplay of genetic disturbances and neuronal and glial pathological processes involving the functioning of the blood-brain barrier, eventually initiated via an ascending toxic process, is the key for attacking vulnerable catecholaminergic neurons such as those in the substantia nigra and locus coeruleus. Neuroprotective therapeutic strategies are difficult to achieve because of the immanent complexity of cell death cascades.