SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects

Abstract

Autism is a neurodevelopmental disorder with a strong genetic component, probably involving several genes. Genome screens have provided evidence of linkage to chromosome 2q31-q33, which includes the SLC25A12 gene. Association between autism and single-nucleotide polymorphisms in SLC25A12 has been reported in various studies. SLC25A12 encodes the mitochondrial aspartate/glutamate carrier functionally important in neurons with highmetabolic activity. Neuropathological findings and functional abnormalities in autism have been reported for Brodmann's area (BA) 46 and the cerebellum. We found that SLC25A12 was expressed more strongly in the post-mortem brain tissues of autistic subjects than in those of controls, in the BA46 prefrontal cortex but not in cerebellar granule cells. SLC25A12 expression was not modified in brain subregions of bipolar and schizophrenic patients. SLC25A12 was expressed in developing human neuronal tissues, including neocortical regions containing excitatory neurons and neocortical progenitors and the ganglionic eminences that generate neocortical inhibitory interneurons. At mid-gestation, when gyri and sulci start to develop, SLC25A12 molecular gradients were identified in the lateral prefrontal and ventral temporal cortex. These fetal structures generate regions with abnormal activity in autism, including the dorsolateral prefrontal cortex (BA46), the pars opercularis of the inferior frontal cortex and the fusiform gyrus. SLC25A12 overexpression or silencing in mouse embryonic cortical neurons also modified dendrite length and the mobility of dendritic mitochondria. Our findings suggest that SLC25A12 overexpression may be involved in the pathophysiology of autism, modifying neuronal networks in specific subregions, such as the dorsolateral prefrontal cortex and fusiform gyrus, at both pre-and postnatal stages.

Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1

“…55 Also overexpression of AGC1 in cell culture has been recently found associated with a biphasic response, characterized initially by enhanced neurite outgrowth, which subsequently slows down and ends in early cell death. 56 This response is seemingly compatible with an initial overproduction of ATP paralleled by a progressive build up of oxidative stress leading to cell damage. Oxidative stress, in addition to lipid and protein oxidation, 55 can also produce genomic instability and stimulate cell cycle progression, pathophysiological events likely to be important in autism pathogenesis 9,57,58 In this regard, the interindividual variability in oxidative damage reported in our study is not at all surprising, as the balance between ROS production and antioxidant agents leaves ample room for genetic and environmental influences.…”

The Mitochondrial Aspartate/Glutamate Carrier AGC1 and Calcium Homeostasis: Physiological Links and Abnormalities in Autism

“…We shall now briefly summarize our findings and examine how they can serve as a paradigm to disclose possible mechanisms underlying mitochondrial dysfunction in ASD. The involvement of AGC1 in neurodevelopmental disorders is not entirely surprising since the modulation of SLC25A12 gene expression has prominent effects on neurodevelopment: an overexpression of SLC25A12 boosting AGC1 transport activity yields enhanced neurite growth in vitro [59]; instead, SLC25A12 disruption alters myelination and neurofilaments [60], further underscoring the critical role played by AGC1 in myelin formation. In our study, we have examined AGC transport rates, AGC1 expression levels, and SLC25A12 genomic DNA and cDNA sequences in post-mortem temporocortical gray matter (Brodmann area 41/42 or 22) of six pairs of nonsyndromic ASD patients and sex-, age-, and post-mortem interval (PMI)-matched controls [58].…”

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

“…Alterations in control of neuritogenesis are always complex, and they may be associated with manifestation of certain symptoms of neurodevelopmental diseases. Postmortem studies of brains of autistic subjects have linked neurite outgrowth to the pathophysiology of autism (Lepagnol-Bestel et al 2008). Moreover, in experimental models, autism-related behavioral deficits were identified in knockout mice lacking the genes coding for neurexins, a family of cell adhesion molecules (Peñagarikano et al 2011).…”