Dynamic Changes of Brain Cilia Transcriptomes across the Human Lifespan

Abstract

Almost all brain cells contain primary cilia, antennae-like microtubule sensory organelles, on their surface, which play critical roles in brain functions. During neurodevelopmental stages, cilia are essential for brain formation and maturation. In the adult brain, cilia play vital roles as signaling hubs that receive and transduce various signals and regulate cell-to-cell communications. These distinct roles suggest that cilia functions, and probably structures, change throughout the human lifespan. To further understand the age-dependent changes in cilia roles, we identified and analyzed age-dependent patterns of expression of cilia’s structural and functional components across the human lifespan. We acquired cilia transcriptomic data for 16 brain regions from the BrainSpan Atlas and analyzed the age-dependent expression patterns using a linear regression model by calculating the regression coefficient. We found that 67% of cilia transcripts were differentially expressed genes with age (DEGAs) in at least one brain region. The age-dependent expression was region-specific, with the highest and lowest numbers of DEGAs expressed in the ventrolateral prefrontal cortex and hippocampus, respectively. The majority of cilia DEGAs displayed upregulation with age in most of the brain regions. The transcripts encoding cilia basal body components formed the majority of cilia DEGAs, and adjacent cerebral cortices exhibited large overlapping pairs of cilia DEGAs. Most remarkably, specific α/β-tubulin subunits (TUBA1A, TUBB2A, and TUBB2B) and SNAP-25 exhibited the highest rates of downregulation and upregulation, respectively, across age in almost all brain regions. α/β-tubulins and SNAP-25 expressions are known to be dysregulated in age-related neurodevelopmental and neurodegenerative disorders. Our results support a role for the high dynamics of cilia structural and functional components across the lifespan in the normal physiology of brain circuits. Furthermore, they suggest a crucial role for cilia signaling in the pathophysiological mechanisms of age-related psychiatric/neurological disorders.

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

“…The length of primary cilia is increased with age in the CA1 and CA3 but not in the dentate gyrus (DG) of rats ( Guadiana et al, 2016 ). Moreover, a recent meta-analysis study suggests that the expression of primary cilia structure and function associated genes shows age-dependent patterns across the human lifespan ( Chen et al, 2021 ). However, how primary cilia are regulated and function during brain aging is still under-studied.…”

Cilia in the Striatum Mediate Timing-Dependent Functions

“…Cilia's dynamic structure, reflected by the vibrant length, morphology, and protein composition, allows cilia to quickly respond to environmental stimuli such as light, mechanical stimuli, pH, and chemical signals (signaling molecules, neurotransmitters, and nutrients) [13][14][15][16][17][18][19]. Although most ciliopathies are associated with cognitive impairments, cilia have only been scarcely investigated for their roles in higherorder cognitive functions [20][21][22][23][24][25].…”