Parkinsonism Sac domain mutation in Synaptojanin-1 affects ciliary properties in iPSC-derived dopaminergic neurons

Abstract

Synaptojanin-1 (SJ1) is a major neuronal-enriched PI(4, 5)P 2 4- and 5-phosphatase implicated in the shedding of endocytic factors during endocytosis. A mutation (R258Q) that impairs selectively its 4-phosphatase activity causes Parkinsonism in humans and neurological defects in mice (SJ1 RQ KI mice). Studies of these mice showed, besides an abnormal assembly state of endocytic factors at synapses, the presence of dystrophic nerve terminals selectively in a subset of nigro-striatal dopamine (DA)-ergic axons, suggesting a special lability of DA neurons to the impairment of SJ1 function. Here we have further investigated the impact of SJ1 on DA neurons using iPSC-derived SJ1 KO and SJ1 RQ KI DA neurons and their isogenic controls. In addition to the expected enhanced clustering of endocytic factors in nerve terminals, we observed in both SJ1 mutant neuronal lines increased cilia length. Further analysis of cilia of SJ1 RQ DA neurons revealed abnormal accumulation of the Ca 2+ channel Ca v 1.3 and of ubiquitin chains, suggesting a defect in the clearing of ubiquitinated proteins at the ciliary base, where a focal concentration of SJ1 was observed. We suggest that SJ1 may contribute to the control of ciliary protein dynamics in DA neurons, with implications on cilia-mediated signaling.

AOP-Anchored Transcriptome Analysis Catalogue Accelerates the Discovery of Environmental Toxicants in Zebrafish

“…Of those genes, disc1 has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. Both downregulation and overexpression of disc1 have been demonstrated to impair the synaptic plasticity and recognition memory by disrupting neural activity. , Exposure to PFOS led to substantial changes in expressions of biomarker genes including interleukin-1β ( IL-1β ) and synaptojanin 1 ( synj1 ) that are related to neurodegeneration. , La also affected the transcriptional expression of these genes, but it was not as pronounced as in the case of PFOS (Table S6). Consequently, these molecular-level findings demonstrate an additional validation of the reliability of the current AATA strategy.…”

“…52,53 Exposure to PFOS led to substantial changes in expressions of biomarker genes including interleukin-1β (IL-1β) and synaptojanin 1 (synj1) that are related to neurodegeneration. 54,55 La also affected the transcriptional expression of these genes, but it was not as pronounced as in the case of PFOS (Table S6). Consequently, these molecular-level findings demonstrate an additional validation of the reliability of the current AATA strategy.…”