Differential modification of dopamine transporter and tyrosine hydroxylase mRNAs in midbrain of subjects with parkinson's, alzheimer's with parkinsonism, and alzheimer's disease

Abstract

The molecular characteristics of midbrain dopamine (DA) neurons have been extensively studied in Parkinson's disease (PD). No such studies of the characteristics of midbrain DA neurons in Alzheimer's disease (AD) or Alzheimer's disease with parkinsonism (AD/Park) have been published. 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 in the ventral tier of the substantia nigra pars compacta (SNpc) of the PD group in accompanied by severe losses in the number of neurons that express TH mRNA and DAT mRNA (74% loss). Remaining neurons show a shift to higher concentrations of TH mRNA but a shift to lower concentrations of DAT mRNA per cell. Hence, there is evidence that compensation in the remaining neurons can elevate concentrations of TH mRNA and lower 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 the SNpc of PD cases. There was no change in TH protein but an elevation of TH mRNA concentrations per neuron without any change in concentrations of DAT mRNA in the AD group. The AD/Park group did not exhibit changes in the level of TH protein, but showed a small loss (26%) of neurons in the SNpc and a greater loss in other regions of the midbrain (43-53%). Remaining DA neurons showed a marked shift to lower concentrations of DAT mRNA per neuron and a nonsignificant shift in cellular concentration of TH mRNA to higher levels. This is consistent with our previous work showing that with AD/Park there is a significant reduction 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 cell 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 proteins.

Delayed increase of tyrosine hydroxylase expression in rat nigrostriatal system after traumatic brain injury

“…The present immunohistochemical studies suggest that TBI did not decrease in the number of TH-positive neurons in the substantia nigra area, a hallmark of PD models. However, the increased appearance of TH in the substantia nigra after TBI is consistent with the clinical observation in PD patients (Joyce et al, 1997) and may reflect increased TH synthesis.…”

“…For example, despite a reduction in TH mRNA-positive neurons, higher levels of TH messenger RNA per neuron were observed in PD patients compared to aged controls (Joyce et al, 1997). Thus, surviving neurons in PD exhibit higher levels of TH mRNA than control neurons.…”

Neurotensin receptors and dopamine transporters: Effects of MPTP lesioning and chronic dopaminergic treatments in monkeys

“…Cellular expression of DAT and tyrosive hydroxylase (TH) mRNAs in the human post-mortem substantia nigra pars compacta are also useful to estimate levels of DA innervation in the nigrostratal tract. In Parkinson's disease, marked losses of TH and DAT mRNAs were observed, the remaining neurons expressing higher levels of TH mRNA and lower levels of DAT mRNA per cell (Harrington et al, 1996;Joyce et al, 1997;Uhl et al, 1994).…”

Dopamine transporter-immunoreactive neurons decrease with age in the human substantia nigra

“…It is of interest that the age-related alteration in DAT expression appears to be similar to that seen in patients with PD. For example, DA neurons express higher levels of TH but lower levels of DAT (Uhl et al, 1994;Joyce et al, 1997) messenger RNA per neuron in PD than aged controls. However, the number of TH mRNA-positive neurons that are DAT mRNA-positive is approximately 60-65% in both PD and age-matched controls , indicative of a shift to type 2 neurons.…”