Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinsons linked-LRRK2 mutant mice DOI Creative Commons
Ebsy Jaimon, Yu‐En Lin, Francesca Tonelli

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 3, 2024

Parkinsons disease-associated, activating mutations in Leucine Rich Repeat Kinase 2 (LRRK2) block primary cilia formation cholinergic and parvalbumin interneurons astrocytes the striatum, decreasing production of GDNF NRTN neuroprotective factors that normally support dopaminergic neuron viability. We show here 3 month-dietary administration MLi-2 LRRK2 kinase inhibitor restores Hedgehog-responsive by these neurons; are also restored on neurons pedunculopontine nucleus. Importantly, we detect recovery striatal processes decreased stress-triggered Hedgehog signaling nigral neurons. Thus, pathogenic LRRK2-driven loss is reversible post-mitotic astrocytes, which suggests early specific inhibitors may have significant therapeutic benefit for patients future.

Language: Английский

Age-related ciliopathy: Obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia DOI Creative Commons
Manami Oya, Yoshiki Miyasaka, Yoshiko Nakamura

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(5), P. 1044 - 1058.e10

Published: March 6, 2024

Obesity is often associated with aging. However, the mechanism of age-related obesity unknown. The melanocortin-4 receptor (MC4R) mediates leptin-melanocortin anti-obesity signaling in hypothalamus. Here, we discovered that MC4R-bearing primary cilia hypothalamic neurons progressively shorten age rats, correlating age-dependent metabolic decline and increased adiposity. This "age-related ciliopathy" promoted by overnutrition-induced upregulation inhibited or reversed dietary restriction knockdown ciliogenesis-associated kinase 1 (CILK1). Forced shortening genetic approaches impaired neuronal sensitivity to melanocortin resulted decreased brown fat thermogenesis energy expenditure appetite, finally developing leptin resistance. Therefore, despite its acute effect, chronic increases susceptibility promoting cilia. study provides a crucial for obesity, which risk syndrome.

Language: Английский

Citations

13
The neuronal cilium – a highly diverse and dynamic organelle involved in sensory detection and neuromodulation DOI Creative Commons
Nathalie Jurisch‐Yaksi, Dagmar Wachten, Jay Gopalakrishnan

et al.

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(5), P. 383 - 394

Published: April 4, 2024

Cilia are fascinating organelles that act as cellular antennae, sensing the environment. gained significant attention in late 1990s after their dysfunction was linked to genetic diseases known ciliopathies. Since then, several breakthrough discoveries have uncovered mechanisms underlying cilia biogenesis and function. Like most cells animal kingdom, neurons also harbor cilia, which enriched neuromodulatory receptors. Yet, how neuronal modulate physiology behavior remains poorly understood. By comparing ciliary biology between sensory central nervous systems (CNS), we provide new perspectives on functions of brain physiology.

Language: Английский

Citations

10
Ultrastructural differences impact cilia shape and external exposure across cell classes in the visual cortex DOI Creative Commons
Carolyn Ott, Russel Torres, T. S. Kuan

et al.

Current Biology, Journal Year: 2024, Volume and Issue: 34(11), P. 2418 - 2433.e4

Published: May 14, 2024

A primary cilium is a membrane-bound extension from the cell surface that contains receptors for perceiving and transmitting signals modulate state activity. Primary cilia in brain are less accessible than on cultured cells or epithelial tissues because they protrude into deep, dense network of glial neuronal processes. Here, we investigated frequency, internal structure, shape, position large, high-resolution transmission electron microscopy volumes mouse visual cortex. Cilia extended bodies nearly all excitatory inhibitory neurons, astrocytes, oligodendrocyte precursor (OPCs) but were absent oligodendrocytes microglia. Ultrastructural comparisons revealed base microtubule organization differed between neurons glia. Investigating cilia-proximal features many directly adjacent to synapses, suggesting poised encounter locally released signaling molecules. Our analysis indicated synapse proximity likely due random encounters neuropil, with no evidence activity as would be expected tetrapartite synapses. The observed class differences synapses largely external length. Many key structural influenced both placement shape and, thus, exposure processes outside cilium. Together, ultrastructure within around suggest formation function across types brain.

Language: Английский

Citations

8
Molecular modulation of aggregation-induced luminescence for improving response sensing of DNA hydrogels DOI

Xuebing Bai,

Chenxi Wang, Lei Huang

et al.

Biosensors and Bioelectronics, Journal Year: 2025, Volume and Issue: 276, P. 117254 - 117254

Published: Feb. 12, 2025

Language: Английский

Citations

1
Permanent deconstruction of intracellular primary cilia in differentiating granule cell neurons DOI Creative Commons
Carolyn Ott, Sandii Constable, Tri Nguyen

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(10)

Published: June 27, 2024

Primary cilia on granule cell neuron progenitors in the developing cerebellum detect sonic hedgehog to facilitate proliferation. Following differentiation, cerebellar cells become most abundant neuronal type brain. While are essential during early developmental stages, they infrequent upon maturation. Here, we provide nanoscopic resolution of situ using large-scale electron microscopy volumes and immunostaining mouse cerebella. In many cells, found intracellular cilia, concealed from external environment. Cilia were disassembled differentiating neurons-in a process call deconstruction-distinct premitotic resorption proliferating progenitors. deconstruction involved unique disassembly intermediates, and, as maturation progressed, mother centriolar docking at plasma membrane. Unlike ciliated neurons other brain regions, our results show which might prevent mitogenic responsiveness. Ciliary could be paradigmatic removal differentiation tissues.

Language: Английский

Citations

7
Postnatal Dynamic Ciliary ARL13B and ADCY3 Localization in the Mouse Brain DOI Creative Commons

Katlyn K. Brewer,

Kathryn M. Brewer, Tiffany T. Terry

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(3), P. 259 - 259

Published: Jan. 30, 2024

Primary cilia are hair-like structures found on nearly all mammalian cell types, including cells in the developing and adult brain. A diverse set of receptors signaling proteins localize within to regulate many physiological developmental pathways, Hedgehog (Hh) pathway. Defects structure, protein localization, function lead genetic disorders called ciliopathies, which present with various clinical features that include several neurodevelopmental phenotypes hyperphagia-associated obesity. Despite their dysfunction being implicated disease states, understanding roles central nervous system (CNS) development has proven challenging. We hypothesize dynamic changes ciliary composition contribute this challenge may reflect unrecognized diversity CNS cilia. The ARL13B ADCY3 established markers is a regulatory GTPase important for regulating trafficking, Hh signaling, adenylyl cyclase. Here, we examine localization perinatal mouse define proportion enriched depending brain region age. Furthermore, identify distinct lengths specific regions male female mice. ARL13B+ become relatively rare age regions, hypothalamic feeding centers, while becomes prominent marker mature It understand endogenous patterns these throughout under different conditions as common be more than initially expected. Understanding regional- developmental-associated signatures condition reveal molecular mechanisms associated commonly observed ciliopathy models like obesity diabetes.

Language: Английский

Citations

5
Understanding the Intricacies of Cellular Mechanisms in Remyelination: The Role of Circadian Rhythm DOI Creative Commons
Yufen Tang, Lu Zhang, Peng Huang

et al.

Neurochemistry International, Journal Year: 2025, Volume and Issue: 183, P. 105929 - 105929

Published: Jan. 5, 2025

Language: Английский

Citations

0
Multicilia dynamically transduce Shh signaling to regulate choroid plexus functions DOI Open Access

Suifang Mao,

Rui Song, Shibo Jin

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by multiciliated epithelial monolayer that regulates CSF production. We demonstrate defective choroid ciliogenesis or Intraflagellar transport yields neonatal hydrocephalus, at least in part, due to increased water channel Aqp1 and ion transporter Atp1a2 expression. multicilia as sensory cilia, transducing both canonical non-canonical Shh signaling. Interestingly, it the signaling represses expression Smo/Gαi/cAMP pathway. exhibit unique ciliary ultrastructure, carrying features of primary motile cilia. Unlike most cilia elongate during maturation, length decreases development, causing decline intensity developing plexus, derepression Atp1a2, ultimately, an Hence, developmental dynamics dampens promote

Language: Английский

Citations

0
Primary ciliary protein kinase A activity in the prefrontal cortex modulates stress in mice DOI
Jiajun Yang, Yingjie Dong, Jing Liu

et al.

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
Multicilia dynamically transduce Sonic Hedgehog signaling to regulate choroid plexus functions DOI Creative Commons

Suifang Mao,

Rui Song, Shibo Jin

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(3), P. 115383 - 115383

Published: March 1, 2025

Highlights•Choroid plexus cilia defects contribute to a neonatal hydrocephalus phenotype•Choroid exhibit distinct ultrastructure resembling primary and motile cilia•Choroid transduce Shh repress water channel ion transporter expression•Developmental dynamics of choroid ciliary length governs the signaling intensitySummaryThe is major site for cerebrospinal fluid (CSF) production, characterized by multiciliated epithelial monolayer that regulates CSF production. We demonstrate defective ciliogenesis or intraflagellar transport yields hydrocephalus, at least in part due increased Aqp1 Atp1a2 expression. multicilia as sensory cilia, transducing both canonical non-canonical Sonic Hedgehog (Shh) signaling. Interestingly, it represses expression Smoothened (Smo)/Gαi/cyclic AMP (cAMP) pathway. Choroid unique ultrastructure, carrying features cilia. Unlike most elongate during maturation, decreases development, causing decline intensity developing plexus, derepression Atp1a2, and, ultimately, Hence, developmental dampens promote production.Graphical abstract

Language: Английский

Citations

0