DIFFERENTIAL MODIFICATION OF DOPAMINE TRANSPORTER AND TYROSINE-HYDROXYLASE MESSENGER-RNAS IN MIDBRAIN OF SUBJECTS WITH PARKINSONS, ALZHEIMERS WITH PARKINSONISM, AND ALZHEIMERS-DISEASE

The molecular characteristics of midbrain dopamine (DA) neurons have b een extensively studied in Parkinson's disease (PD). No such studies o f the characteristics of midbrain DA neurons in Alzheimer's disease (A D) or Alzheimer's disease with parkinsonism (AD/Park) have been publis hed. We examined the levels of tyrosine hydroxylase (TH) protein, and the expression of TH and dopamine transporter (DAT) mRNAs, in midbrain neurons of PD, AD, and AD/Park cases. In PD, the loss of TH protein i n the ventral tier of the substantia nigra pars compacta (SNpc) of the PD group is accompanied by severe losses in the number of neurons tha t express TH mRNA and DAT mRNA (74% loss). Remaining neurons show a sh ift to higher concentrations of TH mRNA but a shift to lower concentra tions of DAT mRNA per cell. Hence, there is evidence that compensation in the remaining neurons can elevate concentrations of TH mRNA and lo wer DAT mRNA. Alternatively, there may be a predilection for a loss of neurons with high levels of DAT mRNA and low TH mRNA levels within th e SNpc of PD cases. There was no change in TH protein but an elevation of TH mRNA concentrations per neuron without any change in concentrat ions of DAT mRNA in the AD group. The AD/Park group did not exhibit ch anges in the level of TH protein, but showed a small loss (26%) of neu rons in the SNpc and a greater loss in other regions of the midbrain ( 43-53%). Remaining DA neurons showed a marked shift to lower concentra tions of DAT mRNA per neuron and a nonsignificant shift in cellular co ncentration of TH mRNA to higher levels. This is consistent with our p revious work showing that with AD/Park there is a significant reductio n in the number of DAT sites located on DA terminals in the striatum, but the midbrain neurons have not died. Our results indicate that the differential regulation of mRNAs encoding TH and DAT is similar in the parkinsonian disorders (PD and AD/Park) even though the degree of cel l death is very different. This might suggest that compensatory events occur in these DA neurons in AD/Park that are similar to those in PD and that result in differential effects on mRNAs encoding TH and DAT p roteins.