Role of upregulation of the KATP channel subunit SUR1 in dopaminergic neuron degeneration in Parkinson's disease

Accumulating evidence suggests that ATP-sensitive potassium (K-ATP) channels play an important role in the selective degeneration of dopaminergic neurons in the substantia nigra (SN). Furthermore, the expression of the K-ATP channel subunit sulfonylurea receptor 1 (SUR1) is upregulated in the remaining nigral dopaminergic neurons in Parkinson's disease (PD). However, the mechanism underlying this selective upregulation of the SUR1 subunit and its subsequent roles in PD progression are largely unknown. In 3-, 6-, and 9-month-old A53T alpha-synuclein transgenic (alpha-SynA53T(+/+)) mice, only the SUR1 subunit and not SUR2B or Kir6.2 was upregulated, accompanied by neuronal damage. Moreover, the occurrence of burst firing in dopaminergic neurons was increased with the upregulation of the SUR1 subunit, whereas no changes in the firing rate were observed except in 9-month-old alpha-SynA53T(+/+) mice. After interference with SUR1 expression by injection of lentivirus into the SN, the progression of dopaminergic neuron degeneration was delayed. Further studies showed that elevated expression of the transcription factors FOXA1 and FOXA2 could cause the upregulation of the SUR1 subunit in alpha-SynA53T(+/+) mice. Our findings revealed the regulatory mechanism of the SUR1 subunit and the role of K-ATP channels in the progression of dopaminergic neuron degeneration, providing a new target for PD drug therapy.

Automated summary

The upregulation of the SUR1 subunit in ATP-sensitive potassium channels is found to play an important role in the selective degeneration of dopaminergic neurons in Parkinson's disease. Delaying the progression of dopaminergic neuron degeneration is possible through interference with SUR1 expression. The elevated expression of transcription factors FOXA1 and FOXA2 has been identified as a mechanism causing the upregulation of the SUR1 subunit.