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

Mitochondria at the crossroads of health and disease DOI Creative Commons
Anu Suomalainen, Jodi Nunnari

Cell, Год журнала: 2024, Номер 187(11), С. 2601 - 2627

Опубликована: Май 1, 2024

Mitochondria reside at the crossroads of catabolic and anabolic metabolism—the essence life. How their structure function are dynamically tuned in response to tissue-specific needs for energy, growth repair, renewal is being increasingly understood. respond intrinsic extrinsic stresses can alter cell organismal by inducing metabolic signaling within cells distal tissues. Here, we review how centrality mitochondrial functions manifests health a broad spectrum diseases aging.

Язык: Английский

Процитировано

122
Single-nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke in male rodents DOI Creative Commons
Daniel Bormann, Michael Knoflach,

Emilia Poreba

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 24, 2024

Neuroglia critically shape the brain´s response to ischemic stroke. However, their phenotypic heterogeneity impedes a holistic understanding of cellular composition early lesion. Here we present single cell resolution transcriptomics dataset acute infarction. Oligodendrocyte lineage cells and astrocytes range among most transcriptionally perturbed populations exhibit infarction- subtype-specific molecular signatures. Specifically, find infarction restricted proliferating oligodendrocyte precursor (OPCs), mature oligodendrocytes reactive astrocytes, exhibiting transcriptional commonalities in injury. OPCs are involved shared immuno-glial cross talk with stroke-specific myeloid cells. Within perilesional zone, osteopontin positive accumulate close proximity CD44

Язык: Английский

Процитировано

11
Primary cilia sense glutamine availability and respond via asparagine synthetase DOI Creative Commons
Maria Elena Steidl, Elisa Agnese Nigro,

Anne Kallehauge Nielsen

и другие.

Nature Metabolism, Год журнала: 2023, Номер 5(3), С. 385 - 397

Опубликована: Март 6, 2023

Abstract Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable integrating multiple signalling cues, but their precise sensory function not fully understood. Here we show that primary respond to nutrient availability adjust length via glutamine-mediated anaplerosis facilitated asparagine synthetase (ASNS). Nutrient deprivation causes elongation, mediated reduced mitochondrial function, ATP AMPK activation independently mTORC1. Of note, glutamine removal replenishment necessary sufficient induce ciliary elongation or retraction, respectively, under stress conditions both in vivo vitro restoring ASNS-dependent glutamate generation. Ift88-mutant lacking glutamine-dependent during stress, due expression activity ASNS base cilia. Our data indicate a role for responding to, possibly sensing, cellular levels stress.

Язык: Английский

Процитировано

23
Cell type mapping reveals tissue niches and interactions in subcortical multiple sclerosis lesions DOI Creative Commons
Celia Lerma-Martin, Pau Badia-i-Mompel, Ricardo O. Ramirez Flores

и другие.

Nature Neuroscience, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 5, 2024

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Inflammation gradually compartmentalized and restricted to specific tissue niches such as lesion rim. However, precise cell type composition niches, their interactions changes between active inactive stages are incompletely understood. We used single-nucleus spatial transcriptomics from subcortical MS corresponding control tissues map types associated pathways nonlesion areas. identified perivascular spaces, inflamed rim or core that with glial scar cilia-forming astrocyte subtype. Focusing on lesions, we uncovered cell–cell communication events myeloid, endothelial types. Our results provide insight into cellular composition, multicellular programs intercellular in along conversion homeostatic dysfunctional state underlying progression MS. Lerma-Martin et al. generated paired RNA sequencing dataset multiple identifying key driving inflammation at

Язык: Английский

Процитировано

8
Bridging lipid metabolism and mitochondrial genome maintenance DOI Creative Commons

C W Boone,

Samantha C. Lewis

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(8), С. 107498 - 107498

Опубликована: Июнь 27, 2024

Язык: Английский

Процитировано

7
Mitochondrial control of ciliary gene expression and structure in striatal neurons DOI Creative Commons
Doğukan Hazar Ülgen, Alessandro Chioino,

Olivia Zanoletti

и другие.

The Journal of Physiology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 18, 2025

Abstract Mitochondria play essential metabolic roles and are increasingly understood to interact with other organelles, influencing cellular function disease. Primary cilia, as sensory signalling crucial for neuronal communication function. Emerging evidence suggests that mitochondria primary cilia may regulate processes, recently shown in brain cells such astrocytes. Here, we investigated whether also neurons, focusing on molecular pathways linking both organelles structural components within cilia. We employed a cross‐species, pathway‐focused approach explore connections between mitochondrial ciliary revealing strong associations suggesting coordinated functionality. Furthermore, found viral‐induced downregulation of the fusion gene mitofusin 2 ( Mfn2 ) dopamine D1 receptor‐expressing medium spiny neurons (D1‐MSNs) nucleus accumbens (NAc) altered expression, Crocc – encoding rootletin showing most pronounced downregulation. This reduction expression was linked decreased levels protein, key component rootlet. Notably, viral‐mediated overexpression restored complexity elongation, without compromising adaptation Our findings provide novel functional mitochondria–cilia interaction specifically striatal D1‐MSNs. These results reveal previously unrecognized role dynamics regulating structure potential implications neuropsychiatric neurodegenerative disease mechanisms. image Key points cell structures known producing energy but emerging regulators components, including antenna‐like involved communication. Previous studies suggest influence function, However, this has not been explored neurons. study shows natural variation correlates rats mice. Reducing (Mfn2), protein mitochondria–endoplasmic reticulum interactions, changes specific pathways, notably Crocc, structure, reduces its product, rootletin, which supports integrity. an important highlighting pathway regulation signalling.

Язык: Английский

Процитировано

1
Primary cilia shape hallmarks of health and aging DOI
Diana F. Silva, Cláudia Cavadas

Trends in Molecular Medicine, Год журнала: 2023, Номер 29(7), С. 567 - 579

Опубликована: Май 1, 2023

Язык: Английский

Процитировано

14
NEKL-4 regulates microtubule stability and mitochondrial health in ciliated neurons DOI Creative Commons
Kaiden M. Power, Ken C. Q. Nguyen,

Andriele Silva

и другие.

The Journal of Cell Biology, Год журнала: 2024, Номер 223(9)

Опубликована: Май 20, 2024

Ciliopathies are often caused by defects in the ciliary microtubule core. Glutamylation is abundant cilia, and its dysregulation may contribute to ciliopathies neurodegeneration. Mutation of deglutamylase CCP1 causes infantile-onset In C. elegans, ccpp-1 loss age-related degradation that suppressed a mutation conserved NEK10 homolog nekl-4. NEKL-4 absent from yet it negatively regulates stability via an unknown, glutamylation-independent mechanism. We show was mitochondria-associated. Additionally, nekl-4 mutants had longer mitochondria, higher baseline mitochondrial oxidation state, ccpp-1∆ mutant lifespan extension response oxidative stress. A kinase-dead nekl-4(KD) ectopically localized cilia rescued degenerating doublet B-tubules. nondegradable nekl-4(PEST∆) resembled with dye-filling B-tubule breaks. The Dyf phenotype depolymerizing kinesin-8 KLP-13/KIF19A. conclude influences activating kinesins promoting homeostasis.

Язык: Английский

Процитировано

6
Single nuclei RNAseq stratifies multiple sclerosis patients into distinct white matter glial responses DOI Creative Commons
Will Macnair,

Daniela Calini,

Eneritz Agirre

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Апрель 9, 2022

Abstract The lack of understanding the cellular and molecular basis clinical genetic heterogeneity in progressive multiple sclerosis (MS) has hindered search for new effective therapies. Here, to address this gap, we analysed 632,000 single nuclei RNAseq profiles 156 brain tissue samples, comprising white matter (WM) lesions, normal appearing WM, grey (GM) lesions GM from 54 MS patients 26 controls. We observed expected changes overall neuronal glial numbers previously described within classical lesion subtypes. found highly cell type-specific gene expression tissue, with distinct differences between WM areas, confirming different pathologies. However, surprisingly, did not observe signatures types, rather a continuum change. This indicates that characterization better reflects abundance than type expression, global disease effect. Furthermore, major biological determinants variability samples relate individual patient effects, types or other metadata. identify four subgroups patterns oligodendrocyte stress and/or maturation, suggestive engagement pathological processes, an additional more variable regenerative astrocyte signature. discovery these patterns, which were also independent cohort, provides framework use biomarkers stratify optimal therapeutic approaches MS, significantly advances our mechanistic highlights need precision-medicine among patients.

Язык: Английский

Процитировано

20
Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration DOI Open Access
Hariprasath Ragupathy,

Manasvi Vukku,

Sandeep Kumar Barodia

и другие.

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(19), С. 14421 - 14421

Опубликована: Сен. 22, 2023

Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which a well-accepted event in pathogenesis of Several common mechanisms are shared by genetically or pathologically distinct diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding translational dysfunction, autophagy activation. Progressive loss neuronal population due increased stress leads mostly accumulation dysfunctional mitochondria. Mitochondrial dysfunction excessive neuroinflammatory responses both sufficient induce pathology neurodegeneration. Therefore, quality control key determinant health survival cells brain. Research has been primarily focused demonstrate significance health, despite important contributions non-neuronal constitute significant portion brain volume. Moreover, morphology function distinctly diverse different tissues; however, little known about their molecular diversity among cell types. dynamics types markedly decide fate overall health; therefore, it not justifiable overlook active contribution facilitating health. In this review article, we aim discuss how remarkable highly synchronized connecting property keeping neurons healthy

Язык: Английский

Процитировано

12