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New Insights From Parkinson’s Research: Inhibition of Shh Signal Transduction as a Possible Early Treatment Approach

Featured Publication, IDG,

Parkinson's disease, formerly known as shaking palsy, is the second most common neurodegenerative disease in Germany after Alzheimer's disease. It affects about 400,000 people in Germany alone and can neither be cured nor can its progression be slowed down. Approximately 90% of patients suffer from the idiopathic form of the disease, the molecular causes of which are poorly understood. This is probably one reason why there is still no causal therapy for this disease, only a symptomatic one.

In addition, Parkinson's disease develops insidiously and often goes unnoticed for decades. When the tremors and muscle stiffness typical of the disease begin, a large number of nerve cells have already been destroyed. The failure to date of disease-modifying interventions in Parkinson's disease may be due in part to the fact that the pathology in established Parkinson's disease is too advanced for the appropriate treatments to be effective, or that the early "unnoticed" pathology is different from the advanced one.

In an interdisciplinary approach, Helmholtz Munich researchers, in cooperation with other Parkinson's researchers, have used human cells obtained from Parkinson's patients to establish a cellular model of early Parkinson's disease. The analysis of this cellular model through single-cell RNA sequencing and the subsequent validation revealed astonishing results. Already in this early model of idiopathic Parkinson's disease, there is a malfunction of the mitochondria. In addition, there is the abnormal expression of primary cilia, a cell organelle responsible for the interaction of the cell with its environment. Both disease-associated phenotypes can be normalized by inhibiting SHH signal transduction.

"We have found that primary cilia and the SHH signaling pathway may play a central role in the development of idiopathic Parkinson's disease. This is new to the field of Parkinson's research. Further research will reveal the molecular dependencies between bioenergetics, primary cilia, and SHH," says the study's first author Dr. Sebastian Schmidt. Prof. Dr. Wolfgang Wurst, corresponding author of the study and director of the Institute of Developmental Genetics adds: "Based on these data, we hope that in the future, by inhibiting SHH signal transduction, mitochondrial and ciliary dysfunctions can be normalized. This would be a first step towards a disease-modulating therapy, which is still lacking for Parkinson's disease."

Original publication:
Schmidt, S., Luecken, M.D., Trümbach, D. et al: Primary cilia and SHH signalling impairments in human and mouse models of Parkinson's disease. Nat Commun 13, 4819 (2022).