Feinstein, T. N. | Search bioRxiv

bioRxiv2021

Mispatterned motile cilia beating causes flow blockage in the epileptic brain

Beating of motile cilia at the brain ventricular surface generates rapid flow in an evolutionary conserved pattern mediating the transport of cerebrospinal fluid, but its functional importance has yet to be demonstrated. Here we show disturbance of this transport may contribute to seizure susceptibility. Mice haploinsufficient for FoxJ1, transcription factor regulating motile cilia exhibited cilia-driven flow blockage and increased seizure susceptibility. Mutations in two epilepsy-associated kinases, Cdkl5 and Yes1, in mice resulted in similar cilia-driven flow blockage and increased seizure susceptibility. We showed this arises from disorganized cilia polarity associated with disruption in the highly organized basal body anchoring meshwork. Together these findings suggest mispatterning of cilia-generated flow may contribute to epilepsy and thus might account for seizures unresponsive to current seizure medications. One sentence summaryEpilepsy is associated with disturbance of cilia motion and mispatterning of fluid transport in the brain ventricles.

neuroscience↗

bioRxiv2021

iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect with 30% mortality from heart failure (HF) in the first year of life, but why only some patients suffer early-HF and its cause remain unknown. Modeling using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) showed early-HF patient iPSC-CM have increased apoptosis, redox stress, and failed antioxidant response. This was associated with mitochondrial permeability transition pore (mPTP) opening, mitochondrial hyperfusion and respiration defects. Whereas iPSC-CM from patients without early-HF had hyper-elevated antioxidant response with increased mitochondrial fission and mitophagy. Single cell transcriptomics showed dichotomization by HF outcome, with mitochondrial dysfunction and endoplasmic reticulum (ER) stress associated with early-HF. Importantly, oxidative stress and apoptosis associated with early HF were rescued by sildenafil inhibition of mPTP opening or TUDCA suppression of ER stress. Together these findings demonstrate a new paradigm for modeling clinical outcome in iPSC-CM, demonstrating uncompensated mitochondrial oxidative stress underlies early HF in HLHS.

cell biology↗