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

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.