The overexpression of RCAN1 gene cause Down syndrome


Researchers at CHU Sainte-Justine and Université de Montréal have discovered a new mechanism involved in the expression of Down syndrome, one of the main causes of intellectual disability and congenital heart defects in children. The study’s findings were published today in Current Biology.

Down syndrome (SD), also called trisomy 21 syndrome, is a genetic condition that affects approximately one in every 800 children born in Canada.

In these individuals, many genes are expressed abnormally at the same time, making it difficult to determine which genes contribute to which differences.

Professor Jannic Boehm’s research team focused on RCAN1, a gene that is overexpressed in the brains of fetuses with Down syndrome.

The team’s work provides insights into how the gene influences the way the condition manifests itself.

Synaptic plasticity, memory and learning

The human brain is made up of hundreds of billions of cells known as neurons.

They communicate with each other through synapses, which are small gaps between neurons. The ability of synapses to strengthen or weaken over time is known as “synaptic plasticity.”

It’s an important biological phenomenon because it’s essential for memory and learning.

“There are two kinds of synaptic plasticity: long-term potentiation, which strengthens synapses and improves interaction between neurons, and long-term depression, which weakens synapses,” said Boehm, a professor at Université de Montréal and researcher at CHU Sainte-Justine.

“We already knew that synaptic plasticity is influenced by certain proteins,” added Anthony Dudilot, one of the study’s first authors.

“For example, calcineurin is inhibited when long-term potentiation is induced, but it’s activated when long-term depression begins.

But the molecular mechanism underlying calcineurin regulation was less clear.”

Down syndrome (SD), also called trisomy 21 syndrome, is a genetic condition that affects approximately one in every 800 children born in Canada.

In these individuals, many genes are expressed abnormally at the same time, making it difficult to determine which genes contribute to which differences.

The research team found that the various signalling pathways that trigger synaptic potentiation or depression converge on RCAN1. They also determined that the gene regulates calcineurin activity by inhibiting or facilitating it.

Given its dual role as an inhibitor/facilitator, the researchers deduced that RCAN1 works as a “switch” that regulates synaptic plasticity, thereby affecting learning and memory.

A better future for all patients

“This is the first time that the molecular mechanism for calcineurin regulation in bidirectional synaptic plasticity has been determined,” said Boehm.

“This breakthrough explains how overexpression of the RCAN1 gene could cause intellectual disabilities in individuals with Down syndrome. It also opens up the possibility of developing innovative treatments for affected patients.”

About the study

“RCAN1 regulates bidirectional synaptic plasticity” was published in Current Biology in February 2020.

The first authors are Anthony Dudilot and Emilie Trillaud-Doppia, PhD candidates supervised by Jannic Boehm. The senior author is Jannic Boehm, PhD, an associate professor at UdeM’s Department of Neurosciences and researcher at CHU Sainte-Justine. The study was backed by the Canadian Institutes of Health Research (CIHR), Fonds de recherche du Québec – Santé (FRQS), the Alzheimer Society of Canada and Université de Montréal.

Down syndrome (DS), or trisomy 21, is the most prevalent chromosomal anomaly accounting for cognitive impairment and intellectual disability (ID).

Neuropathological changes of DS brains are characterized by a reduction in the number of neurons and oligodendrocytes, accompanied by hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS, but underestimated the role of glial cells as pathogenic players. Aberrant or impaired differentiation within the oligodendroglial lineage and altered white matter functionality are thought to contribute to central nervous system (CNS) malformations.

Given that white matter, comprised of oligodendrocytes and their myelin sheaths, is vital for higher brain function, gathering knowledge about pathways and modulators challenging oligodendrogenesis and cell lineages within DS is essential.

This review article discusses to what degree DS-related effects on oligodendroglial cells have been described and presents collected evidence regarding induced cell-fate switches, thereby resulting in an enhanced generation of astrocytes. Moreover, alterations in white matter formation observed in mouse and human post-mortem brains are described.

Finally, the rationale for a better understanding of pathways and modulators responsible for the glial cell imbalance as a possible source for future therapeutic interventions is given based on current experience on pro-oligodendroglial treatment approaches developed for demyelinating diseases, such as multiple sclerosis

The majority of central nervous system (CNS) diseases are characterized by neuronal damage and white matter malfunctions, which can lead to detrimental motor and sensory effects.

Trisomy 21, as an aneuploidy disorder, is characterized by an additional copy of human chromosome 21 (Hsa21) and causes Down syndrome (DS). DS is the most abundant human trisomy, affecting around 1 in 1100 neonates annually [1], making it the most common genetic cause for intellectual disability (ID) [2].

DS patients suffer from several cognitive impairments, accompanied by a low intelligence quotient (IQ) ranging from 30 to 70 [2], which can be attributed to brain abnormalities. In accordance with the neurocentric paradigm, brain research in DS has followed the concept that neuronal dysfunctions primarily lead to neurological diseases [3].

Therefore, much of the DS research aimed at identifying the underlying genetic interventions of altered neurogenesis. This information is essential for unraveling pharmacological approaches to ameliorate cognitive function (summarized in recent reviews [1,4–8]).

Nevertheless, over the last few years consideration has been given to the re-evaluation of the role of astroglial and oligodendroglial lineage cells in CNS pathologies characterized by neurodegeneration [3,9].

Interestingly, several studies in DS indicated a neuro- to gliogenic shift, mainly focusing on the observed bias toward astrocytes [3,4,6,10]. Even though oligodendroglial Cells 2019, 8, 1591; doi:10.3390/cells8121591 Cells 2019, 8, 1591 2 of 19 cells—as a source of CNS myelin sheaths – are essential for higher brain functions by assuring long-term axonal integrity, metabolic and trophic support, and accelerated electrical signal propagation, this crucial cell population has not attracted much attention in DS.

The notion that aberrant oligodendrogenesis may contribute to cognitive impairments and ID in DS is supported by a recent developmental transcriptome analysis of post-mortem human DS brains [11].

Of note, the analysis of this study revealed a dysregulated gene cluster associated with oligodendroglial cell differentiation and myelination, showing that hypomyelination in DS is caused by a cell-autonomous phenomenon in oligodendrocyte development.

To further highlight the importance of the oligodendroglial lineage in DS development, this review article summarizes the current knowledge regarding altered oligodendrogenesis and white matter malformations in human and rodent DS research.

We show that signaling pathways assumed to lead to defective neurogenesis and to a neuro-to astrogenic shift also affect oligodendrogenesis. Such knowledge may help to devise new treatments that aim to improve brain development and ID by stabilization of the oligodendroglial lineage. 2.

Down Syndrome: A Brief Neurological Profile Associated with more than 80 clinical features affecting many organs, both the occurrence (penetrance) and severity (expressivity) of phenotypes vary across the DS population [4].

Nonetheless, certain characteristics, such as facial dysmorphology, reduced brain volume accompanied by ID, and an early-onset Alzheimer’s disease (AD)-like pathology are common in all DS individuals.

This neurological profile is distinctly marked by hypocellularity in the cerebral hemispheres, frontal lobe, temporal cortex, hippocampus, and cerebellum, most likely explained by a complex spatiotemporal perturbation in neurogenesis, resulting in a reduced neuronal cell population and a subsequently altered neuronal connectivity [1,4,6].

Moreover, aberrant astrogliogenesis and changes in several astrocytic marker expression patterns have been demonstrated in DS (reviewed in [3]). Notably, an over-population of astroglial cells in the frontal lobe of DS fetuses [12], as well as in the frontal cortex, calcarine cortex, and mainly hippocampus of infant and adult DS brains [13], has been observed.

At an advanced age, astrogliosis in the amygdala [14], related to the occurrence of senile plaques and neurofibrillary tangles [13] and in areas of basal ganglia calcification [15], was shown to be implicated in DS.

Furthermore, DS brains of old adults are marked by reduced numbers of oligodendrocytes when compared to age-matched individuals [16]. More devastating is the observed hypomyelination in DS, pointing to an impaired myelination process which proceeds until adulthood, as demonstrated by myelin protein expression [11], histological [17,18], or magnetic resonance imaging (MRI) [19] examinations.

Assessed by diffusion tensor imaging (DTI) fractional anisotropy (FA) analysis, white matter in DS patients showed lower fiber density, smaller axonal diameters, and a reduced myelination degree compared to healthy controls [20].

Decreased FA and early white matter damage were particularly observed in the region of the anterior thalamic radiation, the inferior fronto-occipital fasciculum, the inferior longitudinal fasciculum and the corticospinal tract, bilaterally, the corpus callosum (CC), and the anterior limb of the internal capsule [21–23].

Of note, diminished white matter integrity in DS was associated with poorer performance at neuropsychological assessments [20,23]. In this context, recent evidence in animal models suggests that ongoing myelin remodeling is important for behavior, cognition, and learning throughout adulthood [24,25].

Notably, the onset of cognitive deficits in DS is thought to occur in late infancy, becoming more obvious in adolescence [11,26–33]. This time course indeed correlates with the peak of myelination during the first years of life, continuing into young adulthood [34].

Moreover, immunohistochemical analysis for myelin basic protein (MBP) revealed a decreased density of myelinated axons and a generally delayed myelin formation in DS compared to age-matched controls [18], indicating that the oligodendroglial lineage was directly affected upon gene-dosage effects of Hsa21.

Accordingly, a recent multi-region transcriptome analysis of DS and healthy brains spanning from fetal development to adulthood revealed that genes associated with oligodendroglial cell differentiation and myelination are dysregulated in trisomy 21 during late fetal development and the first years of postnatal life [11].

Weighted-gene co-expression network analysis (WGCNA) within this study identified several modules of co-expressed genes, including the module number 43 (M43) which is related to oligodendrocyte development and myelination including, for example, 20 ,30 -cyclic nucleotide-30 -phosphodiesterase (CNPase), proteolipid protein (PLP), Sox10, and G protein coupled receptor 17 (GPR17).

This module exhibited a distinct downregulation throughout the DS neocortex and hippocampus during development [11]. Of note, GPR17, a modulator of oligodendroglial cell maturation [35], is linked to a significantly reduced expression of sorting nexin family member 27 (SNX27) in DS [36], which was demonstrated to impair oligodendroglial precursor cell (OPC) maturation, resulting in myelination deficits in Ts65Dn mice, a mouse model for DS [37].

However, there is much evidence on aberrant oligodendrogenesis correlating with or contributing to DS-related cognitive impairments, but the underlying mechanisms have so far not been investigated in detail.

University of Montreal


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