Association of autism with polyomavirus infection in postmortem brains

[natasa778]

J Neurovirol. 2010 Mar 29. [Epub ahead of print]

Association of autism with polyomavirus infection in postmortem brains.

Lintas C, Altieri L, Lombardi F, Sacco R, Persico AM. Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy.
Abstract

Autism is a highly heritable behavioral disorder. Yet, two decades of genetic investigation have unveiled extremely few cases that can be solely explained on the basis of de novo mutations or cytogenetic abnormalities. Vertical viral transmission represents a nongenetic mechanism of disease compatible with high parent-to-offspring transmission and with low rates of disease-specific genetic abnormalities. Vertically transmitted viruses should be found more frequently in the affected tissues of autistic individuals compared to controls. Our initial step was thus to assess by nested polymerase chain reaction (PCR) and DNA sequence analysis the presence of cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), human herpes virus 6 (HHV6), BK virus (BKV), JC virus (JCV), and simian virus 40 (SV40) in genomic DNA extracted from postmortem temporocortical tissue (Brodmann areas 41/42) belonging to 15 autistic patients and 13 controls. BKV, JCV, and SV40 combined are significantly more frequent among autistic patients compared to controls (67% versus 23%, respectively; P < .05). The majority of positives yielded archetypal sequences, whereas six patients and two controls unveiled single-base pair changes in two or more sequenced clones. No association is present with the remaining viruses, which are found in relatively few individuals (N </= 3). Also polyviral infections tend to occur more frequently in the brains of autistic patients compared to controls (40% versus 7.7%, respectively; P = .08). Follow-up studies exploring vertical viral transmission as a possible pathogenetic mechanism in autistic disorder should focus on, but not be limited to, the role of polyomaviruses.

 

[JillBohr]

Natasa, this is HUGE! Are they ever going to do post-mortem studies on those with CFS/ME? I bet you dollars to donuts that you will see the same results. I wish they would have been able to test for XMRV as well. I would love to know if these subjects had tested positive for XMRV and that is why they have such high viral loads. I hope this another large step in the direction of treating XMRV and getting these viral loads down. I can not believe that we are still focusing on Applied Behaviour therapy on children with autism and psychological therapy on those with ME/CFS when this is clearly a medical condition.

 

[JillBohr]

BKV, JCV, and SV40 combined are significantly more frequent among autistic patients compared to controls (67% versus 23%, respectively; P < .05).

Natasa, I am wondering if we should concentrate on SV40, BKV and JCV? Do these viruses increase calcium levels and what does the combination of all three do?

 

[natasa778]

I wish they would have been able to test for XMRV as well

My feeling is they will, eventually. These Italians rock! - this is their second postmortem study, the first one was looking at mito abnormalities and found evidence not related to genetic makeup + brain calcium overload.

It would be GREAT if they decided to FISH for xmrv in a postmortem study in autism. And to add few pwcs' postmortem samples while at it...

I don't have a useful answer to your second question.

 

[Rosemary]

My feeling is they will, eventually. These Italians rock! - this is their second postmortem study, the first one was looking at mito abnormalities and found evidence not related to genetic makeup + brain calcium overload. ... .

Natasa, Is this the mito study you are referring to ?

Mol Psychiatry. 2010 Jan;15(1):38-52. Epub 2008 Jul 8.

Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1.
Palmieri L, Papaleo V, Porcelli V, Scarcia P, Gaita L, Sacco R, Hager J, Rousseau F, Curatolo P, Manzi B, Militerni R, Bravaccio C, Trillo S, Schneider C, Melmed R, Elia M, Lenti C, Saccani M, Pascucci T, Puglisi-Allegra S, Reichelt KL, Persico AM.

Department of Pharmaco-Biology, University of Bari, Bari, Italy. lpalm@farmbiol.uniba.it

Abstract
Autism is a severe developmental disorder, whose pathogenetic underpinnings are still largely unknown. Temporocortical gray matter from six matched patient-control pairs was used to perform post-mortem biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier (AGC), which participates in the aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is physiologically activated by calcium (Ca(2+)). AGC transport rates were significantly higher in tissue homogenates from all six patients, including those with no history of seizures and with normal electroencephalograms prior to death. This increase was consistently blunted by the Ca(2+) chelator ethylene glycol tetraacetic acid; neocortical Ca(2+) levels were significantly higher in all six patients; no difference in AGC transport rates was found in isolated mitochondria from patients and controls following removal of the Ca(2+)-containing postmitochondrial supernatant. Expression of AGC1, the predominant AGC isoform in brain, and cytochrome c oxidase activity were both increased in autistic patients, indicating an activation of mitochondrial metabolism. Furthermore, oxidized mitochondrial proteins were markedly increased in four of the six patients. Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families, whereas some unaffected siblings may carry a protective gene variant. Therefore, excessive Ca(2+) levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca(2+) homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.

PMID: 18607376 [PubMed - indexed for MEDLINE

 

[Rosemary]

Further information here......
Short Report
Mitochondrial aspartate/glutamate carrier SLC25A12 gene is associated with autism
Joni A. Turunen 1 *, Karola Rehnstrm 1 2, Helena Kilpinen 1, Mikko Kuokkanen 1 2, Elli Kempas 1, Tero Ylisaukko-oja 1 2
1Department of Molecular Medicine and Institute for Molecular Medicine, Finland (FIMM), National Public Health Institute, Helsinki, Finland
2Department of Medical Genetics, University of Helsinki, Finland

email: Joni A. Turunen (joni.turunen@helsinki.fi)

*Correspondence to Joni A. Turunen, Department of Molecular Medicine, National Public Health Institute, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland

Funded by:
Pivikki and Sakari Sohlberg Foundation
Center of Excellence of Disease Genetics of the Academy of Finland
Finnish Cultural Foundation
Cure Autism Now

Keywords
autism • Asperger syndrome • SLC25A12 • association • SNP


Abstract
Two single nucleotide polymorphisms (SNP) within Mitochondrial Aspartate/Glutamate Carrier SLC25A12 gene have recently shown to be strongly associated with autism. Here, we attempted to replicate this finding in two separate Finnish samples with autism spectrum disorders. Family-based association analysis of two SNPs, rs2056202 and rs2292813, previously shown to be associated with autism was performed in two samples with different phenotypic characteristics. The samples included 97 families with strictly defined autism and 29 extended families with Asperger syndrome (AS). We detected association at rs2292813 (FBAT, P=0.0018) in the Finnish autism sample. In, addition other family-based analysis methods supported this finding. By contrast, analysis of the AS sample yielded no evidence for association. This study shows further support that genetic variants within SLC25A12 gene contribute to the etiology of autism.



--------------------------------------------------------------------------------
Received: 6 March 2008; Revised: 23 May 2008; Accepted: 16 June 2008
Digital Object Identifier (DOI)

 

[Rosemary]

Hi Gerwyn and Natasa ,

I hope you don't mind I have some questions please
I am certain that some of the solute carriers also can and do function as retrovirus receptors...do you therefore know more about this specific solute carrier mutation associated with autism.....SLC25A12 ?

Do you think that the SLC25A12 gene could perhaps be a viral/retroviral receptor or perhaps it could be a viral/retroviral transporter ?
Also aren't the SLC normally upregulated as a result of infection ?
I wonder if the SLC25A12 gene in autism is therefore mutated resulting in a loss of function as a result of an infection ?
I would love to hear your thoughts please

 

[Rosemary]

Slc25a12 disruption alters myelination & neurofilaments: a model for hypomyelination

Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders.

BACKGROUND: SLC25A12, a susceptibility gene for autism spectrum disorders that is mutated in a neurodevelopmental syndrome, encodes a mitochondrial aspartate-glutamate carrier (aspartate-glutamate carrier isoform 1 [AGC1]). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate production.

METHODS: We characterized mice with a disruption of the Slc25a12 gene, followed by confirmatory in vitro studies. RESULTS: Slc25a12-knockout mice, which showed no AGC1 by immunoblotting, were born normally but displayed delayed development and died around 3 weeks after birth. In postnatal day 13 to 14 knockout brains, the brains were smaller with no obvious alteration in gross structure. However, we found a reduction in myelin basic protein (MBP)-positive fibers, consistent with a previous report. Furthermore, the neocortex of knockout mice contained abnormal neurofilamentous accumulations in neurons, suggesting defective axonal transport and/or neurodegeneration. Slice cultures prepared from knockout mice also showed a myelination defect, and reduction of Slc25a12 in rat primary oligodendrocytes led to a cell-autonomous reduction in MBP expression. Myelin deficits in slice cultures from knockout mice could be reversed by administration of pyruvate, indicating that reduction in AGC1 activity leads to reduced production of aspartate/N-acetylaspartate and/or alterations in the dihydronicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide(+) ratio, resulting in myelin defects.

CONCLUSIONS: Our data implicate AGC1 activity in myelination and in neuronal structure and indicate that while loss of AGC1 leads to hypomyelination and neuronal changes, subtle alterations in AGC1 expression could affect brain development, contributing to increased autism susceptibility.

2010: Sakurai Takeshi; Ramoz Nicolas; Barreto Marta; Gazdoiu Mihaela; Takahashi Nagahide; Gertner Michael; Dorr Nathan; Gama Sosa Miguel A; De Gasperi Rita; Perez Gissel; Schmeidler James; Mitropoulou Vivian; Le H Carl; Lupu Mihaela; Hof Patrick R; Elder Gregory A; Buxbaum Joseph D
Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders.
Biological psychiatry 2010;67(9):887-94.

 

[JillBohr]

Hey rosemary,

RE: SLC25A12 - According the 2008 Italian study on altered calcium homeostatis, if I am reading the study correctly, the AGC activity has very little to do with the gene and more to do with increased calcium.

 

[JillBohr]

Natasa, Yes, the Italians do rock! I was looking at the authors on these papers and they look like completely different authors. I am thinking about writing them and request they look for XMRV.

 

[natasa778]

AGC activity has very little to do with the gene and more to do with increased calcium.

yes the Italians looked for genetic explanation but could not find any, only functional...

Jill, Persico would probably be the one to contact. Good idea! Him and Sacco were involved in both of those postmortem studies.

 

[Rosemary]

Yes the research by Palmieri et al confirmed that this abnormal mitochondrial function is associated with autism and it could result in a calcium channelopathy.

Mol Psychiatry. 2010 Jan;15(1):38-52. Epub 2008 Jul 8.

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

Palmieri L, Papaleo V, Porcelli V, Scarcia P, Gaita L, Sacco R, Hager J, Rousseau F, Curatolo P, Manzi B, Militerni R, Bravaccio C, Trillo S, Schneider C, Melmed R, Elia M, Lenti C, Saccani M, Pascucci T, Puglisi-Allegra S, Reichelt KL, Persico AM.

 

[natasa778]

abnormal mitochondrial function is associated with autism and it could result in a calcium channelopathy

no, actually the other way round...

 

[Rosemary]

no, actually the other way round...

Thanks Natasa, I'm trying to understand what is happening here...so are you saying that it is the increased calcium in the cells that damages the mitochondria ?
and therefore this then results in a calcium channel channelopathy ?

 

[JillBohr]

Just wanted to add that they also found a higher incidence of SV40, JCV and BK Virus in brain tumours.

http://cebp.aacrjournals.org/content/12/5/460.full

Genomic sequences of the human polyomaviruses, JC virus (JCV) and BK virus (BKV), and simian virus 40 (SV40) have been reported from several types of human brain tumors, but there have been no population-based seroepidemiologic studies to evaluate the association between polyomavirus infection and brain tumors. We conducted a case-control study, nested within a prospective cohort, to investigate the association between antibodies to JCV, BKV, and SV40, as measured in serum collected 122 years before diagnosis and incident primary malignant brain tumors. Brain tumor cases (n = 44) and age-, gender-, and race-matched controls (n = 88) were identified from participants of two specimen banks in Washington County, Maryland. IgG antibodies to the capsid proteins of JCV and BKV were assessed using ELISAs. SV40-neutralizing antibodies were measured using plaque neutralization assays. Similar to the general population, the prevalence of JCV and BKV infection was high in our study population (77 and 85%, respectively). Antibodies to SV40 were less prevalent (11%). The odds ratio for subsequent brain tumor development was 1.46 [95% confidence interval (CI), 0.613.5] for JCV, 0.66 for BKV (95% CI, 0.221.95), and 1.00 for SV40 (95% CI, 0.303.32). Given the high prevalence of JCV and BKV infections and the millions who were potentially exposed to SV40 through contaminated polio vaccines, future studies should attempt to replicate these findings.