Abstract Aims Parkinson's disease (PD) is a progressive and age‐dependent neurodegenerative disease characterised clinically by a variety of motor symptoms and cognitive impairment. PD was initially considered to be a grey matter disease; however, recently, evidence has emerged that white matter changes in PD precede the neuronal loss seen in the grey matter. The cause of these initial white matter changes is yet to be elucidated. Here, we explored whether dysregulated miRNAs and their target mRNA could provide insight into the underlying mechanisms of early white matter changes in PD. Methods We analysed the expression of miRNAs in three different stages of PD through RNA‐sequencing and validated the differential expression of miRNAs through quantitative reverse transcription polymerase chain reaction. With bioinformatic analyses, we predicted target genes of dysregulated miRNAs and investigated their biomarker potential. Finally, in vitro, we confirmed the targetting of the gene SIRT1 by miR‐543. Results We identified 12 dysregulated miRNAs in PD and found that miR‐543 holds potential as a biomarker for late‐stage PD with dementia. We report upregulation of miR‐543 in early PD white matter tissue and downregulation of SIRT1 . In vitro experiments showed that the upregulation of miR‐543 results in the downregulation of SIRT1 in the white matter, but not in the grey matter. Conclusions We validated SIRT1 as a target of miR‐543 in the brain and showed its function as a potential biomarker. Our results highlight the idea that dysregulation of miR‐543 in early PD white matter, resulting in the dysregulation of SIRT1, potentially influencing the early white matter changes observed in PD.