Changes in the brains of babies shortly after birth could help explain why people go on to develop Parkinson’s disease (PD) and why this is particularly common in people with autism spectrum disorder (ASD).
The findings, in Science Advances, suggest a reason why humans are vulnerable to neurodegenerative diseases in a way that is not seen among other primates.
Researchers were surprised to find increased expression in genes associated with PD among humans that was not found in chimps or rhesus monkeys.
Human changes in regulatory DNA operated across two cell lineages, one linked with autism and the other with PD.
“Patients with ASD are also more likely to develop PD, a link that is currently not understood,” commented the researchers, led by Menno Creyghton, PhD, from Erasmus University Medical Center in the Netherlands.
“Our analysis linking the two diseases through a common network could provide insight into common biology between the two diseases.”
Human brains have several differences to those of primates, including a larger volume, more projections between outermost areas, and greater complexity of neurons in the upper layer.
The researchers note that, soon after birth, babies experience protracted brain development that coincides with periods of extensive synaptic modeling.
To investigate differences with our close evolutionary relatives, they conducted a single-cell transcriptomic and epigenomic analysis of human, rhesus macaque, and chimpanzee brain tissue during early postnatal development.
Through this, the team identified human infant–specific programs and cell states that were not observed in adults and correlated these early life processes with susceptibility to PD in aged neurons.
Specifically, Creyghton and co-workers identified human gene expression changes in immature oligodendrocytes enriched in both ASD risk genes and gene expression losses in patients with ASD.
There were also gene expression gains in human babies enriched in PD risk genes for and among genes dysregulated in PD patients.
Both transcriptional programs were part of a core network that contained human-specific sequence changes in regulatory DNA. This lacked cell lineage specificity, operating in both the oligodendrocyte and neuronal lineages, with different downstream targets for each.
In the oligodendrocyte lineage, the downstream target genes were overrepresented in autism risk genes whereas in the neural lineage, PD risk genes were enriched.
“It is therefore possible that these pathologies could be maintained in the human lineage by complex antagonistic interactions across developmental stages,” the authors speculated.
They noted the “unexpected” correlation between human evolution and Parkinson’s disease.
“It has been suggested that humans are exceptionally vulnerable to neurodegenerative diseases including PD as similar disease pathology has not clearly been observed in other primate species,” the team pointed out.
“We show that the human infant–specific expression changes that are overrepresented in PD-deregulated genes are enriched in synaptic developmental genes.
“Imbalances in synaptic function can strongly affect neural vulnerabilities, especially in larger projection neurons. As such, pathological deregulation of such a program may play a role in PD susceptibility.”
