A new commentary article by Santiago Uribe-Cano, PhD candidate, and Andreas H. Kottmann, PhD, Medical Associate Professor at CUNY School of Medicine, describe how recent findings by Dr. Khan and colleagues provide key insights into Parkinson鈥檚 Disease (PD) pathogenesis. ““(1) article breaks down Dr. Khan’s research, published in PNAS in August, 2024, ““(2).
The commentary article describes the relationship between two neurochemicals: dopamine and acetylcholine. Dopamine serves many functions within the brain, one being the regulation of striatal cholinergic neurons – the major producers of acetylcholine. The balanced relationship between dopamine and the cholinergic neurons enables coordinated movement, a major ability lost is PD.
A long standing theory from the 1960s, the “seesaw” theory, suggests that as PD causes dopamine receptors in the brain to degenerate, the level of dopamine present in the brain decreases and the presence of acetylcholine increase causing an imbalance. Dr. Khan’s research demonstrates that the “seesaw” theory does not fully reflect the conditions present in the brain at late-stage PD. In PD postmortem brains, the work by Dr. Khan and colleagues showed a significant loss of cholinergic neurons in late-stage PD. Thus, PD effects both dopamine receptors and cholinergic neurons. Their research then goes farther on to discover that this condition is present in both patients with inherited PD, and those who develop PD not from their genes but through the combination of environmental and genetic factors.
Their findings go further to describe specifically how the breakdown of cilia in cholinergic neuron and astrocytes (star shaped cells that perform many functions within the brain) develops in late-stage PD. Cilia are the 鈥渉air鈥� like structures that protrude from cell bodies, enabling cells to sense and respond to molecular cues. When cilia break down, the cell is less capable of interacting with it鈥檚 environment, impairing its ability to execute聽major functions.
The recent work is based on the team’s previous research, which found that 聽鈥済ain-of-function鈥� mutations in the LRRK2 kinase, commonly associated with PD, disrupt cilia formation. Thus, the breakdown of cilia on cholinergic neurons and astrocytes is a common feature of PD and supports their findings about the loss of striatal dopaminergic projections and cholinergic neurons in patient鈥檚 with late-stage PD.
Remarkably, they also found a similar reduction in the number of astrocytes and cholinergic neurons with cilia among all sporadic PD samples analyzed, suggesting that cilia dysfunction among cholinergic neurons and astrocytes is a common pathological feature of end-stage PD. These morphological observations are congruent with the reduction of cholinergic markers in the brains of PD patients discussed above since the inability to receive crucial signals via the primary cilium can lead to physiological cell stress, attenuation of gene expression, and outright cell degeneration.
These new finds bring greater understanding to the conditions in a patient’s brain that cause PD, and hopefully, assist researchers and clinicians in developing a cure for PD.
Dr. Khan’s lab at 黑料网-Chapel Hill will continue to investigate the role of cilia in age-related neurodegenerative disease.
- Uribe-Cano S, Kottmann AH. The primary cilium of cholinergic neurons may be a linchpin in the progression of Parkinson’s Disease. Proc Natl Acad Sci U S A. 2024 Sep 24;121(39):e2414226121. doi: 10.1073/pnas.2414226121. Epub 2024 Sep 17. PMID: 39288184.
- Khan SS, Jaimon E, Lin YE, Nikoloff J, Tonelli F, Alessi DR, Pfeffer SR. Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinson’s disease. Proc Natl Acad Sci U S A. 2024 Aug 6;121(32):e2402206121. doi: 10.1073/pnas.2402206121. Epub 2024 Aug 1. PMID: 39088390; PMCID: PMC11317616.