Uncovering cilia function in glial development DOI Open Access
Rachel Bear, Tamara Caspary

Annals of Human Genetics, Год журнала: 2023, Номер 88(1), С. 27 - 44

Опубликована: Июль 10, 2023

SUMMARY Primary cilia play critical roles in regulating signaling pathways that underlie several developmental processes. In the nervous system, are known to regulate signals guide neuron development. Cilia dysregulation is implicated neurological diseases, and underlying mechanisms remain poorly understood. research has predominantly focused on neurons overlooked diverse population of glial cells brain. Glial essential during neurodevelopment, their dysfunction contributes disease; however, relationship between function development understudied. Here we review state field highlight cell types where found ciliary functions linked This work uncovers importance raises outstanding questions for field. We poised make progress understanding human contribution diseases.

Язык: Английский

Keeping pace: the primary cilium as the conducting baton of the islet DOI Creative Commons
Olof Idevall‐Hagren, Ceren Incedal Nilsson, Gonzalo Sánchez

и другие.

Diabetologia, Год журнала: 2024, Номер 67(5), С. 773 - 782

Опубликована: Фев. 14, 2024

Abstract Primary cilia are rod-like sensory organelles that protrude from the surface of most mammalian cells, including cells islet, and mounting evidence supports important roles these structures in regulation beta cell function insulin secretion. The abilities cilium arise local receptor activation is coupled to intrinsic signal transduction, ciliary signals can propagate into influence function. Here, we review recent advances studies provide insights intra-islet cues trigger primary signalling; how second messenger generated propagated within cilia; signalling affects We also discuss potential involvement development progression type 2 diabetes, identify gaps our current understanding islet suggestions on further this intriguing structure. Graphical

Язык: Английский

Процитировано

5
snRNA-seq stratifies multiple sclerosis patients into distinct white matter glial responses DOI Creative Commons
Will Macnair,

Daniela Calini,

Eneritz Agirre

и другие.

Neuron, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Язык: Английский

Процитировано

5
HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis DOI Creative Commons
Çağla Cömert, Kasper Kjær-Sørensen, Jakob Hansen

и другие.

Molecular Metabolism, Год журнала: 2024, Номер 88, С. 102009 - 102009

Опубликована: Авг. 14, 2024

Mitochondrial proteostasis is critical for cellular function. The molecular chaperone HSP60 essential cell function and dysregulation of expression has been implicated in cancer diabetes. few reported patients carrying gene variants show neurodevelopmental delay brain hypomyelination. Hsp60 interacts with more than 260 mitochondrial proteins but the functions affected by deficiency are poorly characterized.

Язык: Английский

Процитировано

4
Author response: Astrogliosis And Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction DOI Open Access

Morgane Djebar,

Isabelle Anselme,

Guillaume Pézeron

и другие.

Опубликована: Авг. 14, 2024

Cilia defects lead to scoliosis in zebrafish, but the underlying pathogenic mechanisms are poorly understood and may diverge depending on mutated gene. Here, we dissected of onset a zebrafish mutant for rpgrip1l gene encoding ciliary transition zone protein. fish developed with near-total penetrance asynchronous juveniles. Taking advantage this asynchrony, found that curvature was preceded by ventricle dilations concomitant perturbation Reissner fiber polymerization loss multiciliated tufts around subcommissural organ. Rescue experiments showed Rpgrip1l exclusively required foxj1a-expressing cells prevent axis curvature. Genetic interactions investigations ruled out Urp1/2 levels as main driver rpgrip1 mutants. Transcriptomic proteomic studies identified neuroinflammation associated increased Annexin potential mechanism development Investigating cell types annexin2 over-expression, uncovered astrogliosis, arising glial surrounding diencephalic rhombencephalic ventricles just before increasing time severity. Anti-inflammatory drug treatment reduced severity correlated astrogliosis macrophage/microglia enrichment ventricle. Mutation cep290 another protein also scoliosis. Thus, propose induced perturbed ventricular homeostasis immune activation novel caused cilia dysfunction.

Язык: Английский

Процитировано

4
Astrogliosis and neuroinflammation underlie scoliosis upon cilia dysfunction DOI Creative Commons

Morgane Djebar,

Isabelle Anselme,

Guillaume Pézeron

и другие.

eLife, Год журнала: 2024, Номер 13

Опубликована: Май 14, 2024

Cilia defects lead to scoliosis in zebrafish, but the underlying pathogenic mechanisms are poorly understood and may diverge depending on mutated gene. Here, we dissected of onset a zebrafish mutant for rpgrip1l gene encoding ciliary transition zone protein. fish developed with near-total penetrance asynchronous juveniles. Taking advantage this asynchrony, found that curvature was preceded by ventricle dilations concomitant perturbation Reissner fiber polymerization loss multiciliated tufts around subcommissural organ. Rescue experiments showed Rpgrip1l exclusively required foxj1a -expressing cells prevent axis curvature. Genetic interactions investigations ruled out Urp1/2 levels as main driver rpgrip1 mutants. Transcriptomic proteomic studies identified neuroinflammation associated increased Annexin potential mechanism development Investigating cell types annexin2 over-expression, uncovered astrogliosis, arising glial surrounding diencephalic rhombencephalic ventricles just before increasing time severity. Anti-inflammatory drug treatment reduced severity correlated astrogliosis macrophage/microglia enrichment ventricle. Mutation cep290 another protein also scoliosis. Thus, propose induced perturbed ventricular homeostasis immune activation novel caused cilia dysfunction.

Язык: Английский

Процитировано

3
Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes DOI
Nicolas Leventoux, Satoru Morimoto, Mitsuru Ishikawa

и другие.

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Май 15, 2024

Язык: Английский

Процитировано

3
The senescence-associated secretome of hedgehog-deficient hepatocytes drives MASLD progression DOI Creative Commons
Ji Hye Jun, Kuo Du, Rajesh Kumar Dutta

и другие.

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(19)

Опубликована: Авг. 27, 2024

The burden of senescent hepatocytes correlates with the severity metabolic dysfunction-associated steatotic liver disease (MASLD), but mechanisms driving senescence and how it exacerbates MASLD are poorly understood. Hepatocytes experience lipotoxicity become when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed determine whether secretomes Smo-deficient perpetuate drive progression. RNA-Seq analysis samples from human murine cohorts confirmed that hepatocyte populations in livers were depleted Smo+ cells enriched cells. When fed a choline-deficient, amino acid-restricted high-fat diet (CDA-HFD) induce MASLD, Smo- mice had lower antioxidant markers developed worse DNA damage, senescence, steatohepatitis, fibrosis than did mice. Sera hepatocyte-conditioned medium thymidine phosphorylase (TP), protein maintains mitochondrial fitness. Treating TP reduced lipotoxicity, whereas inhibiting opposite effect exacerbated CDA-HFD-fed conclude inhibition signaling promoted by suppressing production proteins prevent senescence.

Язык: Английский

Процитировано

3
Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease DOI Creative Commons
Phoebe Valdes, Andrew B. Caldwell, Qing Liu

и другие.

Alzheimer s Research & Therapy, Год журнала: 2025, Номер 17(1)

Опубликована: Янв. 4, 2025

Abstract Background PSEN1, PSEN2, and APP mutations cause Alzheimer’s disease (AD) with an early age at onset (AAO) progressive cognitive decline. PSEN1 are more common generally have earlier AAO; however, certain a later AAO, similar to those observed in PSEN2 . Methods We examined whether endotypes exist across these AAO (~ 55 years) using hiPSC-derived neurons from familial (FAD) patients harboring A79V , N141I V717I mechanistically characterized by integrating RNA-seq ATAC-seq. Results identified endotypes, such as dedifferentiation, dysregulation of synaptic signaling, repression mitochondrial function metabolism, inflammation. ascertained the master transcriptional regulators associated including REST, ASCL1, ZIC family members (activation), NRF1 (repression). Conclusions FAD share regulatory changes within varying severity, resulting reversion less-differentiated state. The mechanisms described offer potential targets for therapeutic interventions.

Язык: Английский

Процитировано

0
USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells DOI Creative Commons
Vignesh Srinivasan, Rabah Soliymani, Larisa Ivanova

и другие.

Heliyon, Год журнала: 2025, Номер 11(3), С. e42031 - e42031

Опубликована: Янв. 23, 2025

Ubiquitin specific protease-14 (USP14) is critical for controlling proteostasis disturbed in human disorders, including Parkinson's disease (PD). Here we investigated USP14 the regulation of α-synuclein (α-syn) degradation via proteasome and autophagy. α-Syn pS129 α-syn were elevated gene-deleted SH-SY5Y dopaminergic cells with decreased activity. However, autophagy coordinated lysosomal expression pathways lacking higher levels transcription factor TFEB. There was an increase reactive oxidative species (ROS) elongated mitochondria deficient counteracting stress levels. Phosphoproteomics revealed that phosphorylated at residue S143 reduces its binding to proteasome. Re-expression wild-type phospho-mimetic S143D-USP14 mutant lowered ROS cells. a promising consider PD target through proteasomes neurons.

Язык: Английский

Процитировано

0
Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain DOI Creative Commons
Enrico Bagnoli, Yu‐En Lin, Sophie Burel

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(5)

Опубликована: Янв. 28, 2025

Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced 1 (PINK1) are associated with familial Parkinson’s disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly Parkin ubiquitin (Ub) indirectly induces phosphorylation of a subset GTPases. Herein we have crossed [R1441C] mutant knock-in mice knock-out (KO) report that loss does not impact endogenous LRRK2-mediated nor do see significant effect on PINK1-mediated Ub phosphorylation. In addition, observe pool Rab-specific, protein phosphatase family member 1H phosphatase, is transcriptionally up-regulated recruited to damaged mitochondria, independent or activity. Parallel signaling pathways supported by assessment motor behavioral studies show no evidence genetic interaction mouse lines. Previously showed cilia R1441C herein KO exhibit ciliogenesis defect striatal cholinergic interneurons astrocytes interferes Hedgehog induction glial derived-neurotrophic factor transcription. This exacerbated double-mutant mice. Overall, our analysis indicates activation and/or function along parallel impair ciliogenesis, suggesting convergent mechanism toward PD. Our data suggest reversal defects downstream offers common therapeutic strategy for PD patients, whereas inhibitors currently clinical trials unlikely benefit patients.

Язык: Английский

Процитировано

0