NEW YORK – A team led by investigators at Yale University School of Medicine has characterized brain cells from the prefrontal cortex of Parkinson's disease (PD) patients using multiomics technologies, defining changes that differ from those in individuals with Alzheimer's disease (AD).
"[W]e investigated the prefrontal cortex to obtain an accurate and unbiased assessment of the complex cellular changes associated with PD, as this brain region is affected and exhibits Lewy body pathology in late-stage PD, and because bulk transcriptomic analysis of this region in PD brains indicated the need for cell-type resolution," Le Zhang, a neuroscientist affiliated with Yale University and the Aligning Science Across Parkinson's Collaborative Research Network and the senior author of a study published in Science Translational Medicine on Wednesday, said in an email.
Using Chromium droplet-based single-nucleus RNA sequencing, Zhang and her colleagues assessed gene expression features in almost 77,400 individual cells from the Brodmann area 9 and dorsolateral regions of the prefrontal cortex. The post-mortem brain samples came from half a dozen individuals with PD and six age-matched, unaffected individuals between the ages of 63 and 96.
"We provide a single-cell transcriptomic atlas with integrated proteomic analysis for the prefrontal cortex of post-mortem late-stage Parkinson’s disease human brains," Zhang said, noting that the results "offer a more detailed cellular architecture of the prefrontal cortex, indicating distinct transcriptional changes that correspond with known PD genetics."
By bringing in Lewy body pathology data and label-free quantitative mass spectrometry-based proteomic profiling data on paired samples from the transcriptomic analyses, the investigators flagged PD-related prefrontal cortex features.
These included enhanced levels of alpha-synuclein pathology in samples with lower-than-usual levels of excitatory neuron chaperone expression, and vice versa, "suggesting a possible protective mechanism that may be overwhelmed in PD," Zhang explained.
The team also identified lower-than-usual levels of proteins involved in synaptic processes in prefrontal cortex neurons from PD patients.
A subsequent comparison that brought in published gene expression data from Alzheimer's disease (AD) prefrontal cortex samples pointed to features that differed between AD and PD. Though glial cells appeared to have altered gene expression in both PD and AD, for example, there was an uptick in neuroinflammation and altered interactions between neuron and astrocyte cells that appeared to be specific to individuals with PD.
"The discovery of diminished neuron-astrocyte interactions alongside enhanced neuroinflammation underscores a shift in our understanding of cell-cell communications in PD," Zhang said, noting that "tandem employment of single nucleus transcriptomic studies and unbiased proteomic interrogation of the prefrontal cortex in PD provides invaluable insight into the complex molecular and cellular pathobiology of late-stage PD."
Building on their current findings, the investigators expect to expand their analyses to include samples from earlier stages of PD, including a so-called prodromal stage marked by a rapid eye movement sleep behavior disorder, Zhang explained.
The data will also be analyzed alongside single-cell profiles generated using cerebral spinal fluid samples from prodromal and PD patients. "By correlating the cellular and molecular changes observed in brain tissue with those in CSF, we aim to enhance our understanding of the neuroimmune interactions occurring in the various stages of PD," Zhang said. "This integrative approach will provide valuable insights into the pathophysiological mechanisms at play, potentially identifying biomarkers for early detection and therapeutic targets for intervention and prevention."