Objective: To evaluate the effect of type 2 diabetes (T2D) on gene transcription in Parkinson’s disease (PD) and non-neurodegenerative control brains.

Background: People with T2D are at increased risk of developing PD [1]. T2D is also associated with more rapid motor and cognitive progression in PD [2]. However, the molecular link between these conditions remains elusive. Insulin signalling regulates gene transcription through several mechanisms and a previous post-mortem study identified T2D-associated transcriptome changes in cortical neurons and neurovascular unit cells, mainly involving cell signalling, cancer and infection-related pathways [3,4].

Method: PD (n=6) and control (n=6) cases with T2D were selected from the archives of the Queen Square Brain Bank along with an equal number of non-diabetic PD and control cases, matched for age and gender. Bulk RNA was extracted from middle frontal gyrus (MFG) and middle temporal gyrus (MTG) tissue and gene expression was measured using a molecular barcode counting platform. The expression panel contained 730 genes from 13 canonical cancer-related pathways. Differential gene expression was evaluated using a negative binomial model and linear regression. An unadjusted p<0.05 was considered significant.

Results: In the non-neurodegenerative control group, 29 and 49 significant differentially expressed genes (DEGs) were identified in the MTG and MFG, respectively. In the PD group, 8 and 63 DEGs were identified in the same regions. MAP3K8, HIST1H3H, LAMA1, IL11RA, JAG2, RPS27A, BDNF were significantly differentially expressed in both brain regions in the control group, while PIK3CG, INHBA, KITLG were dysregulated in both regions in the PD group. 7 MFG DEGs were common to both the PD and control groups but there were no shared MTG DEGs.

Conclusion: Our results indicate dysregulation of genes involved in pro-inflammatory interleukin and TNF-α signalling (MAP3K8, PIK3CG, IL11RA), and regulation of synaptic transmission and plasticity (BDNF, INHBA). Dysregulation of these pathways are associated with Parkinson’s disease and warrant further investigation [5,6]. The limited correlation in DEGs between the PD and control groups may reflect differences in T2D phenotype. Indeed, T2D is a heterogeneous condition and further studies using neuronal-derived exosomes or iPSC-derived neurons from well-characterised T2D patients may help overcome this issue [7,8].

References: 1. De Pablo-Fernandez E, Goldacre R, Pakpoor J, et al. Association between diabetes and subsequent Parkinson disease: A record-linkage cohort study. Neurology 2018;91:e139–42.
2. Mollenhauer B, Zimmermann J, Sixel-Döring F, et al. Baseline predictors for progression 4 years after Parkinson’s disease diagnosis in the De Novo Parkinson Cohort (DeNoPa). Mov Disord 2019;34:67–77.
3. Batista TM, Cederquist CT, Kahn CR. The insulin receptor goes nuclear. Cell Res 2019;29:509–11.
4. Bury JJ, Chambers A, Heath PR, et al. Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain. Acta Neuropathologica Communications 2021;9:5.
5. Miller KM, Mercado NM, Sortwell CE. Synucleinopathy-associated pathogenesis in Parkinson’s disease and the potential for brain-derived neurotrophic factor. npj Parkinsons Dis 2021;7:1–9.
6. Tansey MG, Wallings RL, Houser MC, et al. Inflammation and immune dysfunction in Parkinson disease. Nat Rev Immunol 2022; 1–17.
7. Athauda D, Gulyani S, Karnati HK, et al. Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients with Parkinson Disease: A Secondary Analysis of the Exenatide-PD Trial. JAMA Neurol 2019;76:420–9.
8. Batista TM, Jayavelu AK, Wewer Albrechtsen NJ, et al. A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes. Cell Metabolism 2020;32:844-859.e5.

« Back to 2022 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/type-2-diabetes-associated-transcriptomic-changes-in-parkinsons-disease-and-non-neurodegenerative-control-brains/