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Pathogenic LRRK2 mutations cause loss of primary cilia and Neurturin in striatal Parvalbumin interneurons (mice stereology and human brain tile-scan)

Lin, Yu-En1; Jaimon, Ebsy1; Tonelli, Francesca2; Pfeffer, Suzanne1

Published Nov 11, 2024 on Dryad. https://doi.org/10.5061/dryad.z08kprrpx

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Abstract

Parkinson’s disease-associated, activating mutations in LRRK2 kinase block primary cilia formation in cell culture and in specific cell types in the brain. In the striatum which is important for movement control, about half of astrocytes and cholinergic interneurons, but not the predominant medium spiny neurons, lose their primary cilia. Here we show that Parvalbumin interneurons that are inhibitory regulators of movement also lose primary cilia. Without cilia, these neurons are not able to respond to Sonic Hedgehog signals that normally induce the expression of Patched RNA, and their numbers decrease. In addition, glial cell line-derived neurotrophic factor-related Neurturin RNA is significantly decreased. These experiments highlight the importance of Parvalbumin neurons in cilia-dependent, neuroprotective signaling pathways and show that LRRK2 activation correlates with decreased Neurturin production, resulting in less neuroprotection for dopamine neurons.