Relationship among α-synuclein accumulation, dopamine synthesis, and neurodegeneration in Parkinson disease substantia nigra

The histologic hallmark of Parkinson disease (PD) is loss of pigmented neurons in the substantia nigra (SN) and locus ceruleus (LC) with accumulation of a-synuclein (alpha S). It has been reported that tyrosine hydroxylase (TH)-negative pigmented neurons are present in these nuclei of patients with PD. However, the relationship between TH immunoreactivity and as accumulation remains uncertain. We immunohistochernically examined the SN and LC from patients with PD (n = 10) and control subjects (n = 7). A correlation study indicated a close relationship among decreased TH immunoreactivity, US accumulation, and neuronal loss. In addition, 10% of pigmented neu4. tons in the SN and 54.9% of those in the LC contained abnormal US aggregates. Moreover, 82.3% of pigmented neurons bearing as aggregates in the SN and 39.2% of those in the LC lacked TH immunoreactivity, suggesting that pigmented neurons in the SN have a greater tendency to lack TH activity than those in the LC. Recent studies have shown that this decrease of TH activity leads to a decrease of cytotoxic substances and that decreased dopamine synthesis leads to a reduction of cytotoxic alpha S oligomers. Therefore, the decrease of TH immunoreactivity in pigmented neurons demonstrated here can be considered to represent a cytoprotective mechanism in PD.