Christian González-Billault

• PhD Sciences. Molecular Cell Biology
• Professor at University of Chile

Therapy-induced senescence (TIS) alters calcium (Ca²⁺) flux and Mitochondria-ER Contact Sites (MERCS), revealing critical vulnerabilities in senescent cells. In this study, TIS was induced using Doxorubicin and Etoposide, resulting in an increased MERCS contact surface but a significant reduction in ER-mitochondria Ca²⁺ flux. Mechanistically, TIS c...

NMDA Receptors (NMDARs) have essential functions in the nervous system, including neuronal maturation, neurotransmission, synaptic plasticity, learning, and memory. Following membrane depolarization and glutamate activation, NMDARs mediate Ca2+ influx into neurons, activating Ca2+ signaling cascades with key roles in neuronal function. However, no...

Background The content of circulating exosomes has been observed to be altered in response to changes in physiological and pathological conditions, and they are detectable in different human fluids such as blood. Studies focused on the quantification of Aβ and tau proteins, as molecules contained within exosomes, suggest that they are related with...

The regenerative potential of developing cortical axons following injury depends on intrinsic mechanisms, such as axon-autonomous protein synthesis, that are still not fully understood. An emerging factor in this regenerative process is the bi-directional interplay between microtubule dynamics and structural proteins of the axonal endoplasmic retic...

Ageing is usually associated with physiological decline, increased mental health issues, and cognitive deterioration, alongside specific changes in the gut microbiome. However, the relationship between the neuroactive potential of the gut microbiome and mental health and cognition among the elderly remains less explored. This study examines a cohor...

Background Only few studies of Allostatic Load (AL) have been conducted in Latin/Hispanic populations, and even fewer performed in South American cohorts. Here, we replicated a recently proposed algorithm to derive an AL index in a Chilean cohort of cognitive healthy adults. Methods Using data from the GERO cohort (n = 166, age 76.92 ± 5.07 years,...

Introduction White matter hyperintensities (WMH) in Alzheimer’s disease (AD) have traditionally been associated with cerebrovascular diseases. Amyloid β (Aβ) deposition reportedly contributes to WMHs; however, this relationship remains unclear in dementia-free subjects with cognitive complaints (CC). Here, we explored the relationship between WMHs...

Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on...

This study investigates the state of calcium (Ca ²⁺ ) flux and Mitochondria-ER contact sites (MERCS) on Therapy-Induced Senescence (TIS). TIS cells-induced by Doxorubicin and Etoposide increase their MERCS contact surface but exhibit a decreased ER-mitochondria Ca ²⁺ flux. TIS cells show decreased levels of IP3R isoforms and a decreased interaction...

Background Genome‐wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. Method We performed a GWAS on sporadic Alzheimer’s disease (AD) including 540 patients and 852 controls from Argentina and Chile. We explored the variants associated with AD in Eur...

INTRODUCTION Genome‐wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the Europ...

Aging is a complex biological process that compromises brain function and neuronal network activity, leading to cognitive decline and synaptic dysregulation. In recent years, a cyclic Ketogenic Diet (KD) has emerged as a potential treatment to ameliorate cognitive decline by improving memory in aged mice after long term administration. However, the...

Dysregulated central-energy metabolism is a hallmark of brain aging. Supplying enough energy for neurotransmission relies on the neuron-astrocyte metabolic network. To identify genes contributing to age-associated brain functional decline, we formulated an approach to analyze the metabolic network by integrating flux, network structure and transcri...

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) operates as a centra...

Neuronal polarization is a complex molecular process regulated by intrinsic and extrinsic mechanisms. Nerve cells integrate multiple extracellular cues to generate intracellular messengers that ultimately control cell morphology, metabolism, and gene expression. Therefore, second messengers' local concentration and temporal regulation are crucial e...

Astrocytes are active participants in the performance of the Central Nervous System (CNS) in both health and disease. During aging, astrocytes are susceptible to reactive astrogliosis, a molecular state characterized by functional changes in response to pathological situations, and cellular senescence, characterized by loss of cell division, apopto...

INTRODUCTION, Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS, we performed a GWAS on sporadic Alzheimer's disease (AD) including 540 patients and 852 controls from Argentina and Chile. We explored the variants associated with AD in...

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer’s disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) is an ER-located kin...

The gut microbiota influence neurodevelopment, modulate behavior, and contribute to neurodegenerative disorders. Several studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinson’s disease (PD) fecal samples. Therefore, we investigated whether A.muciniphila conditioned medium (CM) could initiate α-synuclein (αSy...

Brain aging is characterized by several molecular and cellular changes grouped as the hallmarks or pillars of aging, including organelle dysfunction, metabolic and nutrition-sensor changes, stem cell attrition, and macromolecular damages. Separately and collectively, these features degrade the most critical neuronal function: transmission of inform...

Epidemiological studies demonstrate that arsenic exposure is associated with cognitive dysfunction. Experimental arsenic exposure models showed learning and memory deficits and molecular changes resembling the functional and pathologic neurodegeneration features. The present work focuses on hippocampal pathological changes in Wistar rats induced by...

Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endop...

Background: The notion that the gut microbiota plays a role in neurodevelopment, behavior and outcome of neurodegenerative disorders is recently taking place. A number of studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinson’s disease (PD) fecal samples. Nevertheless, a functional link between A. muciniphila...

A Correction to this paper has been published: https://doi.org/10.1038/s41556-021-00673-2.

In Alzheimer's disease (AD), hippocampal hyperactivation is already present at early stages of the disorder, in some cases, even when the individual is still asymptomatic. Neuronal hyperexcitability has been described to occur before the deposition of amyloid beta plaques in mouse models of AD and has been attributed to an imbalance between excitat...

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean...

The acquisition of neuronal polarity is a complex molecular process that depends on changes in cytoskeletal dynamics and directed membrane traffic, regulated by the Rho and Rab families of small GTPases, respectively. However, during axon specification, a molecular link that couples these protein families has yet to be identified. In this paper, we...

Endocytic recycling is an intracellular process that returns internalized molecules back to the plasma membrane and plays crucial roles not only in the reuse of receptor molecules but also in the remodeling of the different components of this membrane. This process is required for a diversity of cellular events, including neuronal morphology acquis...

Background With the global population aging and life expectancy increasing, dementia has turned a priority in the health care system. In Chile, dementia is one of the most important causes of disability in the elderly and the most rapidly growing cause of death in the last 20 years. Cognitive complaint is considered a predictor for cognitive and fu...

The SARS-CoV-2 global pandemic will disproportionately impact countries with weak economies and vulnerable populations including people with dementia. Latin American and Caribbean countries (LACs) are burdened with unstable economic development, fragile health systems, massive economic disparities, and a high prevalence of dementia. Here, we unders...

Impaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various model...

Neural development is a complex process that involves critical events, including cytoskeleton dynamics and selective trafficking of proteins to defined cellular destinations. In this regard, Smad Anchor for Receptor Activation (SARA) is an early endosome resident protein, where perform trafficking- associated functions. In addition, SARA is also in...

Impaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various model...

Mitochondria are highly dynamic organelles constantly undergoing fusion and fission. Ca²⁺ regulates many aspects of mitochondrial physiology by modulating the activity of several mitochondrial proteins. We previously showed that inhibition of constitutive IP3R-mediated Ca²⁺ transfer to the mitochondria leads to a metabolic cellular stress and event...

Aging is a natural process that includes several changes that gradually make organisms degenerate and die. Harman’s theory proposes that aging is a consequence of the progressive accumulation of oxidative modifications mediated by reactive oxygen/nitrogen species, which plays an essential role in the development and progression of many neurodegener...

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the most common neurodegenerative early-onset dementias. Despite the fact that both conditions have a very distinctive clinical pattern, they present with an overlap in their cognitive and behavioral features that may lead to misdiagnosis or delay in diagnosis. The current review intend...

Neurons are highly complex cells that heavily rely on intracellular transport to distribute a range of functionally essential cargoes within the cell. Post-translational modifications of tubulin are emerging as mechanisms for regulating microtubule functions, but their impact on neuronal transport is only marginally understood. Here, we have system...

The acquisition of neuronal polarity is a complex molecular process that involves several different cellular mechanisms that need to be finely coordinated to define the somatodendritic and axonal compartments. Amongst such mechanisms, cytoskeleton and membrane dynamics control both the morphological transitions that define neuronal polarity acquisi...

Platelets are anucleate cells that circulate in blood and are essential components of the hemostatic system. During aging, platelet numbers decrease and their aggregation capacity is reduced. Platelet dysfunctions associated with aging can be linked to molecular alterations affecting several cellular systems that include cytoskeleton rearrangements...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calciu...

Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability. It is produced by mutation of the Fmr1 gene that encodes for the Fragile Mental Retardation Protein (FMRP), an important RNA-binding protein that regulates the expression of multiple proteins located in neuronal synapses. Individuals with FXS exhibit abnormal sen...

In the version of this Article originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Article.

Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a signalling network known as the unfolded protein response (UPR). Here, we identified filamin A as a major binding partner of the ER stress transducer IRE1α. Filamin A is an actin crosslinking factor involved in cytoskeleton remodelling. We show that IRE1α controls actin cytos...

Age is the main risk factor for the onset of neurodegenerative diseases. A decline of mitochondrial function has been observed in several age-dependent neurodegenerative diseases and may be a major contributing factor in their progression. Recent findings have shown that mitochondrial fitness is tightly regulated by Ca²⁺ signals, which are altered...

Physiological levels of ROS are important for several processes in the nervous system, ranging from neuronal precursors proliferation, to axonal guidance and neurotransmission. ROS also support neurite outgrowth and axonal specification, but the mechanisms by which ROS are able to shape neurons remain unknown. We recently showed that NADPH oxidase...

The participation of reactive oxygen species (ROS) generated by NOX1 and NOX2/NADPH oxidase has been documented during inflammatory pain. However, the molecular mechanism involved in their activation is not fully understood. We reported earlier a key role of Cyclin-dependent kinase 5 (Cdk5) during inflammatory pain. In particular, we demonstrated t...

Historically, ROS have been considered toxic molecules, especially when their intracellular concentration reaches high values. However, physiological levels of ROS support crucial cellular processes, acting as second messengers able to regulate intrinsic signaling pathways. Specifically, both the central and peripheral nervous systems are especiall...

Abstract-Population aging is among the most important global transformations. Compared to European and North American countries, Chile is among the countries with the fastest growth of life expectancy at birth during recent decades. The aging of Chile's population is related to the improvement of living conditions, but also entails risks that tend...

The purinergic P2X2 receptor (P2X2R) is an ATP-gated ion channel widely expressed in the nervous system. Here, we identified a putative Cdk5 phosphorylation site in the full-size variant P2X2aR (372TPKH375), which is absent in the splice variant P2X2bR. We therefore investigated the effects of Cdk5 and its neuronal activator, p35, on P2X2aR functio...

Alzheimer's disease (AD) is characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and neuronal death. Aggregated amyloid‐β (Aβ) induces inflammation and oxidative stress, which have pivotal roles in the pathogenesis of AD. Hepcidin is a key regulator of systemic iron homeostasis. Recently, an anti‐inflammatory respon...

The cover image, by Pablo Muñoz-Llancao et al., is based on the Research Article Microtubule-regulating proteins and cAMP-dependent signaling in neuroblastoma differentiation, DOI: 10.1002/cm.21355.

Neurons are highly differentiated cells responsible for the conduction and transmission of information in the nervous system. The proper function of a neuron relies on the compartmentalization of their intracellular domains. Differentiated neuroblastoma cells have been extensively used to study and understand the physiology and cell biology of neur...

Neurons communicate with each other through their axons and dendrites. However, a full characterization of the molecular mechanisms involved in axon and dendrite formation is still incomplete. Neurite outgrowth requires the supply of membrane components for surface expansion. Two membrane sources for axon outgrowth are suggested: Golgi secretary ve...

CDK5 is a serine/threonine kinase that is involved in the normal function of the adult brain and plays a role in neurotransmission and synaptic plasticity. However, its over-regulation has been associated with Tau hyperphosphorylation and cognitive deficits. Our previous studies have demonstrated that CDK5 targeting using shRNA-miR provides neuropr...

Significance statement: While axon outgrowth requires membrane supply for surface expansion, the molecular mechanisms regulating the membrane transport in growing axons remains unclear. Here, we demonstrate that GRAB, a guanine nucleotide exchange factor for Rab8, is a novel regulator of axon outgrowth. GRAB promotes the axonal membrane transport...

Significance statement: High levels of ROS are frequently associated with oxidative stress and disease. In contrast, physiological levels of ROS, mainly sustained by the NADPH oxidase (NOX) complex, promote neuronal development and axonal growth. However, the mechanisms by which ROS shape neurons have not been described. Our work suggests that NOX...

Scientific Reports 6 : Article number: 30069 10.1038/srep30069 ; published online: 18 July 2016 ; updated: 02 September 2016 In this Article, an additional affiliation for Felipe A. Court has been omitted.

Protein phosphorylation, catalyzed by protein kinases, is the main posttranslational modification in eukaryotes, regulating essential aspects of cellular function. Using mass spectrometry techniques, a profound knowledge has been achieved in the localization of phosphorylated residues at proteomic scale. Although it is still largely unknown, the pr...

The capacity of the nervous system to generate neuronal networks relies on the establishment and maintenance of synaptic contacts. Synapses are composed of functionally different presynaptic and postsynaptic compartments. An appropriate synaptic architecture is required to provide the structural basis that supports synaptic transmission, a process...

Microtubule-associated protein 1B (MAP1B) is expressed predominantly during the early stages of development of the nervous system, where it regulates processes such as axonal guidance and elongation. Nevertheless, MAP1B expression in the brain persists in adult stages, where it participates in the regulation of the structure and physiology of dendr...

Unlabelled: Rab35 is a key protein for cargo loading in the recycling endosome. In neuronal immortalized cells, Rab35 promotes neurite differentiation. Here we describe that Rab35 favors axon elongation in rat primary neurons in an activity-dependent manner. In addition, we show that the p53-related protein kinase (PRPK) negatively regulates axona...

Significance statement: Axonal regeneration is a response of injured nerve cells critical for nerve repair in human spinal cord injury. Understanding the molecular mechanisms controlling nerve repair by Galectin-1, may be critical for therapeutic intervention. Our results show that Galectin-1; in its dimeric form, interferes with hydrogen peroxide...

Cyclin‐dependent kinase 5 ( CDK 5) plays important roles in synaptic function. Its unregulated over‐activation has been, however, associated with neurodegeneration in Alzheimer's disease. Our previous studies revealed that CDK 5 silencing ameliorates tauopathy and spatial memory impairment in the 3xTg AD mouse model. However, how CDK 5 targeting af...

Actin and its ability to polymerize into dynamic filaments is critical for the form and function of cells throughout the body. While multiple proteins have been characterized as affecting actin dynamics through non-covalent means, actin and its protein regulators are also susceptible to covalent modifications of their amino acid residues. In this r...

Brain-derived neurotrophic factor (BDNF) and its receptors TrkB and p75 regulate dendritic and axonal growth during development and maintenance of the mature nervous system; however, the cellular and molecular mechanisms underlying this process are not fully understood. In recent years, several advances have shed new light on the processes behind t...

Neurons are highly polarized cells that contain specialized subcellular domains involved in information transmission in the nervous system. Specifically, the somatodendritic compartment receives neuronal inputs while the axons convey information through the synapse. The establishment of asymmetric domains requires a specific delivery of components,...

The generation of abnormally high levels of reactive oxygen species ( ROS ) is linked to cellular dysfunction, including neuronal toxicity and neurodegeneration. However, physiological ROS production modulates redox‐sensitive roles of several molecules such as transcription factors, signaling proteins, and cytoskeletal components. Changes in the fu...

We reported earlier that TNF-α, a proinflammatory cytokine implicated in many inflammatory disorders causing orofacial pain increases Cdk5 activity, a key kinase involved in brain development and function and recently in pain signaling. To investigate a potential mechanism underlying inflammatory pain in trigeminal ganglia (TG), we engineered a tra...

Neuronal death in Parkinson's disease (PD) is often preceded by axodendritic tree retraction and loss of neuronal functionality. The presence of non-functional but live neurons opens therapeutic possibilities to recover functionality before clinical symptoms develop. Considering that iron accumulation and oxidative damage are conditions commonly fo...

Neurites restored by chelator treatment contain the presynaptic marker synaptophysin. Mesencephalic cells were treated for 24 h with 0.5 μM MPP+ followed by treatment for 48 h with 5 μM DFO, 50 μM DFP or 10 μM DPD. Cells were co-stained for TH (green) and synaptophysin (red). Nuclei labeling with TOPRO (blue) gives an account of the total cell popu...

Synthesis strategy for 7DH and 7MH. Scheme 1: synthesis of 7DH. Reagents and conditions: (a) (CH2O)n, ethanol, 40°C, 10 min; (b) 8-hydroxyquinoline, reflux, 6 h. Scheme 2: synthesis of 7MH. Reagents and conditions: (a) (CH2O)n, morpholine, ethanol, 40°C, 10 min; (b) 8- hydroxyquinoline, reflux, 6 h. Purity of both 7DH and 7MH was <98% as determined...

A proper balance between chemical reduction and oxidation (known as redox balance) is essential for normal cellular physiology. Deregulation in the production of oxidative species leads to DNA damage, lipid peroxidation and aberrant post-translational modification of proteins, which in most cases induces injury, cell death and disease. However, phy...

Acquisition of neuronal polarity is a complex process involving cellular and molecular events. The second messenger cAMP is involved in axonal specification through activation of protein kinase A. However, an alternative cAMP-dependent mechanism involves the exchange protein directly activated by cAMP (EPAC), which also responds to physiological ch...

Reactive oxygen species (ROS) produced by the NADPH oxidase (NOX) complex play important physiological and pathological roles in neurotransmission and neurodegeneration, respectively. However, the contribution of ROS to molecular mechanisms involved in neuronal polarity and axon elongation is not well understood. In this work, we found that loss of...

P35 AND RAC1 CONTRIBUTE TO NEUROPROTECTION FOLLOWING CDK5 RNAI: CDK5 plays an important role in neurotransmission and synaptic plasticity in the normal function of the adult brain, and dysregulation can lead to Tau hyperphosphorylation and cognitive impairment. In a previous study, we demonstrated that RNAi knock down of CDK5 reduced the formation...

Low voltage-activated (LVA) T-type Ca2+ channels activate in response to subthreshold membrane depolarizations and therefore represent an important source of Ca2+ influx near the resting membrane potential. In neurons, these proteins significantly contribute to control relevant physiological processes including neuronal excitability, pacemaking and...

Prenatal stress causes predisposition to cognitive and emotional disturbances and is a risk factor towards the development of neuropsychiatric conditions like depression, bipolar disorders and schizophrenia. The extracellular protein Reelin, expressed by Cajal-Retzius cells during cortical development, plays critical roles on cortical lamination an...

Kinesin-5 is a slow homotetrameric motor protein best known for its essential role in the mitotic spindle, where it limits the rate at which faster motors can move microtubules. In neurons, experimental suppression of kinesin-5 causes the axon to grow faster by increasing the mobility of microtubules in the axonal shaft, as well as the invasion of...

The functions of microtubule-associated protein 1B (MAP1B) have historically been linked to the development of the nervous system, based on its very early expression in neurons and glial cells. Moreover, mice in which MAP1B is genetically inactivated have been used extensively to show its role in axonal elongation, neuronal migration and axonal gui...

The universal second messenger cyclic AMP (cAMP) is generated upon stimulation of Gs protein-coupled receptors, such as the β2 -adrenergic receptor (β2 -AR), and leads to the activation of protein kinase A (PKA), the major cAMP effector protein. PKA oscillates between an on and off state and thereby regulates a plethora of distinct biological respo...

Protein phosphorylation is the most common post-translational modification that regulates several pivotal functions in cells. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase which is mostly active in the nervous system. It regulates several biological processes such as neuronal migration, cytoskeletal dynamics, axonal...

Microtubule-associated protein B is a cytoskeleton protein consisting of heavy and light (LC) chains that play important roles in the regulation of neuronal morphogenesis and function. LC1 is also well known to interact with diverse ionotropic receptors at postsynapse. Much less is known, however, regarding the role of LC1 at presynaptic level wher...

Neuronal cells are characterized by the presence of two confined domains, which are different in their cellular properties, biochemical functions and molecular identity. The generation of asymmetric domains in neurons should logically require specialized membrane trafficking to both promote neurite outgrowth and differential distribution of compone...