Primary cilia and ciliary signaling pathways in aging and age-related brain disorders

Ma, Rong; Kutchy, Naseer A.; Chen, Liang; Meigs, Douglas D.; Hu, Guoku

doi:10.1016/j.nbd.2021.105607

Cited by 61 publications

(61 citation statements)

References 187 publications

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“…Loss of TTBK2 has been reported to permit basal body docking to the plasma membrane while impeding transition zone formation and ciliary shaft elongation (May et al ., 2021). Moreover, emerging studies suggest that abnormalities in the length and frequency of primary cilia could be a key regulator in brain diseases (Ma et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Modulation of Tau Tubulin Kinases (TTBK1 and TTBK2) Impacts Ciliogenesis

Potjewyd

Chaikuad

Smith

et al. 2022

Preprint

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SUMMARYTau tubulin kinase 1 and 2 (TTBK1 and TTBK2) are highly homologous kinases that are expressed and mediate disease-relevant pathways predominantly in the brain. Distinct roles for TTBK1 and TTBK2 have been delineated. While efforts have been devoted to characterizing the impact to TTBK1 inhibition in diseases like Alzheimer’s disease and amyotrophic lateral sclerosis, TTBK2 inhibition has been less explored. TTBK2 serves a critical function during cilia assembly. Given the biological importance of these kinases, we designed a targeted library from which we identified several chemical tools that engage TTBK1 and TTBK2 in cells and inhibit their downstream signaling. Indolyl pyrimidinamine 10 significantly reduced the expression of primary cilia on the surface of human induced pluripotent stem cells (iPSCs). Furthermore, analog 10 phenocopies TTBK2 KO in iPSCs, confirming an essential role for TTBK2 in ciliogenesis.

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Section: Introductionmentioning

confidence: 99%

Modulation of Tau Tubulin Kinases (TTBK1 and TTBK2) Impacts Ciliogenesis

Potjewyd

Chaikuad

Smith

et al. 2022

Preprint

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“…In the PC, GliA proteins will either serve as a "reserve pool" for HH signal transduction or become phosphorylated and processed into the GliR form (Pak and Segal, 2016;Bangs and Anderson, 2017). The PC also plays a role in other signal transduction pathways, such as WNT/bcatenin and TGFb signaling (Ma et al, 2022). SHH is the sole HH protein in the developing and adult mammalian brain, and has therefore been implicated in a variety of neurodevelopmental processes and neurodegenerative diseases (Brodski et al, 2019;Yang et al, 2021).…”

Section: Shh Signalingmentioning

confidence: 99%

“…In the PC, GliA proteins will either serve as a “reserve pool” for HH signal transduction or become phosphorylated and processed into the GliR form ( Pak and Segal, 2016 ; Bangs and Anderson, 2017 ). The PC also plays a role in other signal transduction pathways, such as WNT/b-catenin and TGFb signaling ( Ma et al, 2022 ).…”

Section: Developmental Factors Required For Mda Neuron Survival In Th...mentioning

confidence: 99%

Developmental pathways linked to the vulnerability of adult midbrain dopaminergic neurons to neurodegeneration

Prakash

2022

Front. Mol. Neurosci.

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The degeneration of dopaminergic and other neurons in the aging brain is considered a process starting well beyond the infantile and juvenile period. In contrast to other dopamine-associated neuropsychiatric disorders, such as schizophrenia and drug addiction, typically diagnosed during adolescence or young adulthood and, thus, thought to be rooted in the developing brain, Parkinson’s Disease (PD) is rarely viewed as such. However, evidences have accumulated suggesting that several factors might contribute to an increased vulnerability to death of the dopaminergic neurons at an already very early (developmental) phase in life. Despite the remarkable ability of the brain to compensate such dopamine deficits, the early loss or dysfunction of these neurons might predispose an individual to suffer from PD because the critical threshold of dopamine function will be reached much earlier in life, even if the time-course and strength of naturally occurring and age-dependent dopaminergic cell death is not markedly altered in this individual. Several signaling and transcriptional pathways required for the proper embryonic development of the midbrain dopaminergic neurons, which are the most affected in PD, either continue to be active in the adult mammalian midbrain or are reactivated at the transition to adulthood and under neurotoxic conditions. The persistent activity of these pathways often has neuroprotective functions in adult midbrain dopaminergic neurons, whereas the reactivation of silenced pathways under pathological conditions can promote the survival and even regeneration of these neurons in the lesioned or aging brain. This article summarizes our current knowledge about signaling and transcription factors involved in midbrain dopaminergic neuron development, whose reduced gene dosage or signaling activity are implicated in a lower survival rate of these neurons in the postnatal or aging brain. It also discusses the evidences supporting the neuroprotection of the midbrain dopaminergic system after the external supply or ectopic expression of some of these secreted and nuclear factors in the adult and aging brain. Altogether, the timely monitoring and/or correction of these signaling and transcriptional pathways might be a promising approach to a much earlier diagnosis and/or prevention of PD.

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“…The typical conformation of its axoneme is constituted by nine pairs of post-translational, acetylated peripheral microtubules, which are arranged according to its motility status. Non-motile, primary cilia are present in mammalian cells (i.e., fibroblasts, epithelial and muscle cells) [ 44 ], which have a 9 + 0 arrangement of microtubules within their axoneme; conversely, the motile cilia contain a 9 + 2 microtubule arrangement [ 2 , 21 , 45 , 46 , 47 ]. Generically, the cilium is rooted at its base by a basal body, which is derived from the centriole of the centrosome [ 48 ], the latter structure being essential for nucleating the mitotic spindle during cell division.…”

Section: Nomenclature Clarifying Morphological Structuresmentioning

confidence: 99%

“…Cilia are reported to be associated with quiescent cells, while cells that are involved in the cell cycle are non-ciliated (this is because the basal body of cilia forms the centrosomal bodies during cell division, and only after cells enter their quiescent phase do these centriole-derived basal bodies become available for ciliogenesis). Cilia are described as hair-like and/or flagellar structures that form on the cell surfaces of eukaryotes through the process of ciliogenesis [ 47 , 53 ]. Postulated cilia of the vascular endothelium are reported to extend into the lumen of the blood vessel and respond to sensory stimuli (i.e., extracellular stimuli) [ 29 , 45 ].…”

Section: Nomenclature Clarifying Morphological Structuresmentioning

confidence: 99%

The Ism between Endothelial Cilia and Endothelial Nanotubules Is an Evolving Concept in the Genesis of the BBB

Mentor

Fisher

2022

IJMS

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The blood–brain barrier (BBB) is fundamental in maintaining central nervous system (CNS) homeostasis by regulating the chemical environment of the underlying brain parenchyma. Brain endothelial cells (BECs) constitute the anatomical and functional basis of the BBB. Communication between adjacent BECs is critical for establishing BBB integrity, and knowledge of its nanoscopic landscape will contribute to our understanding of how juxtaposed zones of tight-junction protein interactions between BECs are aligned. The review discusses and critiques types of nanostructures contributing to the process of BBB genesis. We further critically evaluate earlier findings in light of novel high-resolution electron microscopy descriptions of nanoscopic tubules. One such phenotypic structure is BEC cytoplasmic projections, which, early in the literature, is postulated as brain capillary endothelial cilia, and is evaluated and compared to the recently discovered nanotubules (NTs) formed in the paracellular spaces between BECs during barrier-genesis. The review attempts to elucidate a myriad of unique topographical ultrastructures that have been reported to be associated with the development of the BBB, viz., structures ranging from cilia to BEC tunneling nanotubules (TUNTs) and BEC tethering nanotubules (TENTs).

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Primary cilia and ciliary signaling pathways in aging and age-related brain disorders

Cited by 61 publications

References 187 publications

Modulation of Tau Tubulin Kinases (TTBK1 and TTBK2) Impacts Ciliogenesis

Modulation of Tau Tubulin Kinases (TTBK1 and TTBK2) Impacts Ciliogenesis

Developmental pathways linked to the vulnerability of adult midbrain dopaminergic neurons to neurodegeneration

The Ism between Endothelial Cilia and Endothelial Nanotubules Is an Evolving Concept in the Genesis of the BBB

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