Cholinergic circuit genes in the healthy brain are differentially expressed in regions that exhibit gray matter loss in Parkinson’s disease

Abstract

Structural covariance networks are able to identify functionally organized brain regions by gray matter volume covariance. In Parkinson’s disease, the posterior cingulate network and anterior cingulate network showed decreased gray matter and therefore we examined the underlying molecular processes of these anatomical networks in the healthy brain. Whole brain transcriptomics from post-mortem samples from healthy adults, revealed upregulation of genes associated with serotonin, GPCR, GABA, glutamate, and RAS signaling pathways in these PD-related regions. Our results also suggest involvement of the cholinergic circuit, in which genes NPPA, SOSTDC1, and TYRP1 may play a protective role. Furthermore, both networks were associated with memory and 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)

“…In addition, prior work from our group showed up-weighting of genes related to synaptic signalling and chemical synaptic transmission in regions showing loss of connectivity in Parkinson's patients at risk of dementia (Zarkali et al, 2020) as well as in regions with increased cortical iron deposition in PD (Thomas et al, 2021). In this way, regional variation in expression of genes relating to synaptic transmission is emerging as a common factor from studies, including by Keo et al (2021), using varying technologies and acquiring imaging data from different PD cohorts, suggesting that it is likely to be of significance in neurodegeneration in PD. Interestingly, Keo et al (2021) found enrichment of the differentially expressed genes in cholinergic cell markers.…”

“…To investigate the biological processes and cell types that may be driving selective vulnerability of the cingulate cortex in PD, Keo et al (2021) (de Schipper et al, 2017). These networks are replicable and at least partly explained by patterns of regional gene expression (Alexander-Bloch et al, 2013;Romero-Garcia et al, 2018), although their neurobiological basis is not fully understood.…”

“…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.…”

“…They then examined the function and cellular composition of these differentially overexpressed genes. Keo et al (2021) found that highly expressed genes in cingulate networks were enriched in pathway and gene ontology terms related to synaptic transmission, particularly neurotransmitter-mediated signalling. Alpha-synuclein is important in neurotransmitter release (Cabin et al, 2002), and accumulation of alpha-synuclein oligomers has been associated with synaptic dysfunction (Diógenes et al, 2012;Rockenstein et al, 2014).…”

“…In this way, regional variation in expression of genes relating to synaptic transmission is emerging as a common factor from studies, including by Keo et al (2021), using varying technologies and acquiring imaging data from different PD cohorts, suggesting that it is likely to be of significance in neurodegeneration 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.…”