Cingulate networks associated with gray matter loss in Parkinson's disease show high expression of cholinergic genes in the healthy brain

Abstract

Structural covariance networks are able to identify functionally organized brain regions by gray matter volume covariance across a population. We examined the transcriptomic signature of such anatomical networks in the healthy brain using postmortem microarray data from the Allen Human Brain Atlas. A previous study revealed that a posterior cingulate network and anterior cingulate network showed decreased gray matter in brains of Parkinson's disease patients. Therefore, we examined these two anatomical networks to understand the underlying molecular processes that may be involved in Parkinson's disease. Whole brain transcriptomics from the healthy brain revealed upregulation of genes associated with serotonin, GPCR, GABA, glutamate, and RAS‐signaling pathways. Our results also suggest involvement of the cholinergic circuit, in which genes NPPA, SOSTDC1, and TYRP1 may play a functional role. Finally, both networks were enriched for genes associated with neuropsychiatric disorders that overlap with Parkinson's disease symptoms. The identified genes and pathways contribute to healthy functions of the posterior and anterior cingulate networks and disruptions to these functions may in turn contribute to the pathological and clinical events observed in Parkinson's disease.

Beyond dopamine: Further evidence of cholinergic dysfunction in Parkinson's disease (Commentary on Keo et al., 2021)

“…To investigate the biological processes and cell types that may be driving selective vulnerability of the cingulate cortex in PD, Keo et al. (2021) examined the anterior and posterior cingulate structural covariate networks previously identified by de Schipper et al. (2017) as showing reduced integrity in PD.…”

“…Interestingly, Keo et al. (2021) found enrichment of the differentially expressed genes in cholinergic cell markers. Although cell types were derived from mouse and not a purely single‐cell dataset (Mancarci et al., 2017), limiting interpretability, this enrichment was consistently seen using two different analyses methods.…”

“…In this article by Keo et al. (2021), the authors examined differential regional gene expression in the anterior and posterior cingulate structural covariate networks (patterns of covariance of grey matter density) of the healthy human brain. They demonstrate a number of highly expressed genes in the cingulate networks which show reduced grey matter integrity in PD, compared to the rest of the cortex.…”

“…In this issue of EJN, Keo et al. (2021) leverage this differential regional and network involvement by examining regional differences in underlying gene expression between two structural covariate networks (patterns of covariance in grey matter morphology) that show disproportionate grey volume atrophy in PD: the anterior and posterior cingulate networks.…”

“…Using data from the Allen Human Brain Atlas (Hawrylycz et al., 2015), Keo et al. (2021) compared gene expression in the healthy human brain between the two cingulate networks and the remaining seven structural covariance networks that are less affected in PD. They identified 144 genes that were highly expressed in both cingulate networks (200 highly expressed genes in the posterior cingulate and 269 highly expressed genes in the anterior cingulate network) but not in other networks.…”