Autism Spectrum Disorder (ASD) refers to a speci c category of
neurodevelopmental impairments characterized by repetitive behaviors and
dif culties in communication and social interaction [1]. Autism, or ASD, is
currently estimated to affect 1 in 59 children; a prevalence that has continued to
rise over the past several decades [2]. Although there is currently no consensus on
the development of ASD, it is understood as a complex disorder caused by a
combination of genetic and environmental factors [3]. Improvements in ways to
analyze genetic information, such as genomic technology (technology used to
analyze the sequence of DNA), have expedited the discovery of the factors that
increase the susceptibility of developing autism. Of these factors, those involved in
the process of calcium signaling within cells have become a compelling candidate
in the physiological processes associated with ASD [3].
In intracellular signaling, speci c signaling molecules within a cell act as chemical
messengers, inducing certain physiological responses in that cell. In intracellular
calcium signaling, Ca2+ ions act as the signaling molecules and are involved in
critical neurological functions such as cell secretion, cell death, and excitation of
nerve cells to transmit impulses [4]. Many research efforts have begun to focus on
the mitochondria, a major intracellular calcium buffer that uses signaling to
communicate dynamically with the endoplasmic reticulum (ER), a major calcium
store within cells. This communication is particularly vital for integrating
electrochemical messages with cellular metabolism in many reactions that occur
within the cell [5]. Dysfunction in mitochondrial Ca2+ signaling have been
implicated in autism, as well as in many other neurologic disorders such as
Parkinson's and Alzheimer's disease [6,7].
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The Gargus lab at the University of California, Irvine is composed of six
researchers that are currently investigating calcium signalling in the hopes of
nding ASD biomarkers (physiological properties that act as indicators of the
disease). The team is a part of the Center for Autism Research and Translation
(CART) and believes that the goal of CART is to “understand the causes of autism
and to facilitate collaborations between researchers of multiple disciplines to allow
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Autism Spectrum Disorder Research at the University of California, Irvine
Today, the team is focusing their attention on calcium ions as biologic markers for
ASD. Rachel noted that “much of our recent research has pointed to a dysfunction
in IP3-mediated calcium signaling as an indicator for the disorder and our ndings
that identi ed this dysfunction can be further developed into more intricate cell
studies to study the exact chemical mechanisms involved in producing the physical
attributes in autistic individuals” [8]. Although there is a plethora of people
conducting research on autism with many different causes being looked at, the
Gargus lab is one that is set apart from the rest. Unlike many labs worldwide, the
Gargus lab has the unique advantage of being a part of CART and being one of the
few “labs who are speci cally focused on calcium signaling networks in autism”
[8]. However, it is not about who nds the biomarker rst, but rather about
collaborative efforts with institutions and labs worldwide.
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Autism is a highly complex disorder. The diversity of its physical characteristics
and genetic makeup has made it extremely dif cult to study and develop
correlations between speci c genes and how they manifest physically. However,
Rachel believes that “advancements in genetic sequencing and neurotechnology
may allow us to overcome many of the limitations in research that we have
previously encountered” [8]. Whether it is looking into calcium signaling or
nding a genetic biomarker, one thing is for certain, the combination of works
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us to take novel approaches that uniquely distinguishes our facility from other
research institutions” [8]. Previously, the Gargus lab used specialized microscopy
to test broblast cells derived from skin samples of patients who had autism due to
a single defective gene. Fibroblast cells, which are commonly found in connective
tissue, produce important structural bers. The results of the study showed that the
release of calcium from the ER through speci c calcium channels was impaired in
the tested broblast cells [9,10]. In a current ongoing study, the Gargus lab is now
investigating whether this impaired intracellular Ca2+ signalling is also affected by
a dysfunction in mitochondrial activity. Through this study, the Gargus lab hopes to
nd a genetic biomarker for ASD and further improve our knowledge of the
mechanisms behind the disease. Rachel Nguyen, a member of the lab, was able to
sit down with us and discuss the study and its signi cance.
from those all around the globe and their collaborative efforts are bringing the
world one step closer to identifying the indicators of autism.
References:
Nguyen, R. (2017) Connecting genetic calcium channel variants to
molecular pathways in pathogenesis of Autism Spectrum Disorders.
Proposal. 1: 1-3.
2. “Autism Spectrum Disorder (ASD).” Center for Disease Control and
Prevention, 26 April 2018, https://www.cdc.gov/ncbddd/autism/data.html
3. Chaste, P. Marion, L. (2012) Autism risk factors: genes, environment, and
gene-environment interactions. Dialogues in clinical
neuroscience, 14:281-291.
4. Zundorf, G., Resier, G., (2011) Calcium Dysregulation and Homeostasis of
Neural Calcium in the Molecular Mechanisms of Neurodegenerative
Diseases Provide Multiple Targets for Neuroprotection. Antioxidants &
Redox Signaling, 14:1275-88.
5. Gargus, J. J. (2009). Genetic calcium signaling abnormalities in the central
nervous system: seizures, migraine, and autism. Annals of the New York
Academy of Sciences, 1151:133-156.
6. Giorgi, C., Agnoletto, C., Bononi, A., Bonora, M., De Marchi, E.,
Marchi, S., Pinton, P. (2012). Mitochondrial calcium homeostasis as
potential target for mitochondrial medicine. Mitochondrion. 12:77-85.
7. Chunyan, G., Li, S., Xueping, C., Danshen, Z. (2013) Oxidative stress,
mitochondrial damage and neurodegenerative diseases. Neural Regeneration
Research. 8:2003-2014.
8. Nguyen, Rachel. Personal interview. 25 Nov. 2018.
9. Schmunk, G., Boubion, B., Smith, F., Gargus, J. (2015) Shared functional
defect in IP3R-mediated calcium signaling in diverse monogenic autism
syndromes. Translational Psychiatry. 5:643.
10. Schmunk, G., Nguyen, R., Ferguson, D., Kumar, K., Parker, I., Gargus,
J. (2017) High-throughput screen detects calcium signaling dysfunction in
typical sporadic autism spectrum disorder. Scienti c Reports. 7:40740.
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