PT  - JOURNAL ARTICLE
AU  - Khan, Shahzad S.
AU  - Jaimon, Ebsy
AU  - Lin, Yu-En
AU  - Nikoloff, Jonas
AU  - Tonelli, Francesca
AU  - Alessi, Dario R.
AU  - Pfeffer, Suzanne R.
TI  - Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinson’s disease
AID  - 10.1101/2024.01.15.575737
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.01.15.575737
4099  - http://biorxiv.org/content/early/2024/01/16/2024.01.15.575737.short
4100  - http://biorxiv.org/content/early/2024/01/16/2024.01.15.575737.full
AB  - Activating LRRK2 mutations cause Parkinson’s disease. Previously, we showed that cholinergic interneurons and astrocytes but not medium spiny neurons of the dorsal striatum lose primary cilia in LRRK2 mutant mice. Single nucleus RNA sequencing shows that cilia loss in cholinergic interneurons correlates with higher LRRK2 expression and decreased glial derived neurotrophic factor transcription. Nevertheless, much higher LRRK2 expression is seen in medium spiny neurons that have normal cilia in mice and humans. In parallel with decreased striatal dopaminergic neurite density, LRRK2 G2019S neurons show increased autism-linked CNTN5 adhesion protein expression; glial cells show significant loss of ferritin heavy chain. Human striatal tissue from LRRK2 pathway mutation carriers and idiopathic Parkinson’s disease show similar cilia loss in cholinergic interneurons and astrocytes and overall loss of such neurons. These data strongly suggest that loss of cilia in specific striatal cell types decreases neuroprotection for dopamine neurons in mice and human Parkinson’s disease.Teaser Cilia loss in Parkinson’s disease decreases dopaminergic neuroprotection due to inability to sense Hedgehog signalsCompeting Interest StatementThe authors have declared no competing interest.