Reply to Liu et al.: HNF4A and PTBP1 expression in the brain of neurodegenerative disease patients.

We thank Liu et al. (1) for their comments on our manuscript in which hepatocyte nuclear factor 4 alpha (HNF4A) and polypyrimidine tract binding protein 1 (PTBP1) are identified as potential dynamic biomarkers for Parkinson’s disease (PD) (2). In our study, transcriptomic and network-based metaanalysis identified HNF4A and PTBP1 as the most significant up-regulated and down-regulated genes, respectively, in blood of PD. Given the involvement of HNF4A in glucose metabolism and PTBP1 in insulin regulation, our findings provide a molecular rationale for the impaired insulin signaling observed in PD patients. Liu et al. (1) investigated whether HNF4A and PTBP1 expression was regulated by common genetic variants, known as expression quantitative trait loci (eQTLs). They used two large eQTLs datasets comprising multiple brain regions from healthy and neurodegenerative disease controls. In brain regions from neurologically normal individuals, PTBP1 was regulated by a trans-acting single nucleotide polymorphism (SNP) (rs11146131) that mapped to JAKMIP3, also known as NECC2, a molecular scaffold that is involved in the maintenance of the tyrosine kinase receptor (trkA)–nerve growth factor (NGF) signaling. Of note, TrkA–NGF signaling is involved in insulin regulation (3). In addition, several cis-SNPs regulated HNF4A in different brain regions from late-onset Alzheimer’s disease (AD) and Huntington’s disease (HD) patients. For instance, among the group of cis-acting SNPs regulating HNF4A is rs6031596, which has been shown to regulate the activity of serum gamma-glutamyl transferase (GGT) in humans (4). Interestingly, GGT protects against oxidative stress by making cysteine available for regeneration of intracellular gluthanione and its altered activity is associated with an increased risk for diabetes (4). In this regard, diabetes, impaired insulin signaling, and glucose metabolism have been related to the pathogenesis of several neurodegenerative diseases including AD and PD (5). Although the analysis reported by Liu et al. (1) was performed using brain datasets from individuals with neurodegenerative diseases other than PD, their findings are important because the identification of eQTLs can shed light on the molecular mechanisms associated with the altered expression of HNF4A and PTBP1 observed in PD. Furthermore, PD and AD share common molecular networks (6); therefore, it is plausible to consider that dysregulation of HNF4A and PTBP1 is involved in several neurodegenerative diseases in which glucose and insulin signaling is disrupted. It will be interesting in future studies to evaluate the eQTLs identified by Liu et al. (1) in tissues from PD patients. Collectively, a comprehensive understanding of the genetic variants responsible for regulating disease-associated factors in different tissues and conditions could provide insight into the molecular mechanisms leading to neurodegeneration.