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ATP Facilitates Study of Mitochondrial and Synaptic Dysfunction in Autism

July 09, 2008

The Autism Tissue Program (ATP) is a brain tissue donor program sponsored by Autism Speaks that provides brain tissue to researchers worldwide. Three recently published papers relied on this precious resource to understand the impact of mitochondrial dysfunction in autism and the role of synapses in autism.

The first two reports were authored by ATP Principal Investigator Prof. Michel Simonneau, M.D., Ph.D., at INSERM, the French National Institute for Health and Medical Research, in Paris, France with colleagues there and in the United States. (1, 2)

Dr. Simonneau's article, titled "SLC25A12 Expression is Associated With Neurite Outgrowth and is Upregulated in the Prefrontal Cortex of Autistic Subjects", was chosen as the cover article for the prestigious journal Molecular Psychiatry. Simmoneau's group pursued the genetic analysis of cells in two brain regions of interest in autism, the cerebellum and Brodmann's area (BA) 46 -- an area of the cerebral cortex responsible for motor planning, organization and regulation, integration of sensory information, and regulation of intellectual function and action. Specifically, they were interested in following a trail of evidence their group reported several years ago suggesting the importance of a genetic programming mechanism for the mitochondrial aspartate/glutamate carrier that functions in energy production and cell metabolism. Their first evidence for the potential involvement of this gene (SLC25A12) in autism came from a study they had performed using DNA obtained from blood samples from a subset of subjects from Autism Speaks' Autism Genetic Resource Exchange (AGRE). The authors had previously shown that the SLC25A12 gene on chromosome 2 is important in neurodevelopment. This gene 'turns on' early in human fetal neuronal tissues which then impacts the region of the prefrontal cortex associated with early exaggerated postnatal growth in children with autism.

In the second paper, titled "Convergent Evidence Identifying MAP/Microtubule Affinity Regulating Kinase 1 (MARK1) as a Susceptibility Gene for Autism", the authors similarly explored another susceptibility locus for autism, a gene called MARK1 (microtubule affinity-regulating kinase 1), also found using AGRE samples. The MARK1 gene produces an enzyme called a kinase that regulates mitochondrial trafficking in microtubules within the axons or dendrites. These microtubules function like a conveyor belt for information. In both studies, the authors discovered an over-expression of the two genes in the prefrontal cortex but not in the cerebellum.

In the neuron, with its often long axonal processes and dendritic elaborations that are crucial for synaptic (cell to cell) communication, mitochondria are vital suppliers of the energy-rich adenine triphosphate molecule, as well as a source of calcium for a functional synapse, a process dependent on proper SLC25A12 gene activity. Further, the mitochondria need to be moved to regions of high energy demand like the synapse -- this process is known as mitochondrial trafficking, considered a function of the MARK1 gene. The authors point out that another gene, PRKCB1, previously identified by their group as a susceptibility gene for autism spectrum disorders in AGRE families, encodes a protein that interacts with microtubules and is considered to be involved in trafficking mitochondria to dendrites as well. They suggest that mitochondria at the synapse supply energy in part for transport of messenger RNA to make and replenish important synaptic proteins, allowing the developing brain to make functional connections.

The significance of these findings is important in the context of mitochondrial function and a host of physical and cognitive problems that can occur with dysfunction of mitochondria. Newspaper articles about mitochondrial diseases have been appearing due to publicity surrounding the federal litigation in the case of Hanna Poling, a child who received routine vaccination at 19 months and was later diagnosed with autism but, additionally, has a mitochondrial disease.

Read a meeting summary for a recently held, NIH sponsored symposium dedicated to the discussion of mitochondrial encephalopathies and their potential relationship to autism.

Mitochondria are small organelles in cells that break down sugars and fats from food using oxygen (in a process called oxidative phosphorylation). The energy from this process is stored in a molecule called, coincidentally, ATP (the aforementioned adenosine triphosphate molecule) and is used to fuel most cellular processes. Many genes contribute to this key metabolic process. Mitochondria have their own DNA, called mtDNA, with genes that work in conjunction with genes from the cell's nuclear DNA for ATP (energy) production as well as coding instructions on how to build, break down and recycle proteins. ATP made in mitochondria provides the main source of power for muscle cell contraction and nerve cell firing. Thus, muscle cells and nerve cells are especially sensitive to mitochondrial defects. The combined effects of energy deprivation contribute to the main symptoms of mitochondrial myopathies (disease of skeletal muscle caused by mitochondrial dysfunction) and encephalopathies (conditions characterized by altered brain function). Malfunction of mitochondria is suspected in a variety of complex diseases including diabetes, heart disease, stroke, multiple sclerosis, Alzheimer's disease as well as autism related disorders such as chromosome 15q duplication.

These and other recent science results have raised the question many researchers are now focusing on -- whether autism is basically a disease of the synapse (brain cell to cell connection point) caused by multiple different disruptions that affect the formation or function of the synapse itself. The authors cite mutations linked to autism in genes that make excitatory synaptic proteins (neuroligins, neurexins and SHANK3) that could diminish the integrity of these synapses.

Another mechanism may play a role at the synapse according to the authors of the third paper, titled "Heterogeneous Dysregulation of microRNAs across the Autism Spectrum" (3). MicroRNAs (miRNAs) are abundant in the brain, and are capable of regulating the production of proteins coded by messenger RNA (mRNA). There are from 500-1000 different miRNAs in human cells and these short RNA sequences can bind to many different longer RNA strands and inhibit or alter protein synthesis. The authors indicate that miRNAs exert a broad regulatory control over the expression of many different proteins involved in brain development. They point out that these short pieces of RNA, with ~ 21 nucleotides, have a role in several complex neurological diseases such as Tourette's and Fragile X syndromes. Turning their attention to autism, they compared the expression of 466 human miRNAs from postmortem cerebellar cortex tissue of individuals with ASD (n = 13) and a control set of non-autistic cerebellar samples (n = 13) that were provided by the Autism Tissue Program. The result was 28 significantly dysregulated miRNAs in the autism donor brain specimens.

The predicted targets of some of these dysregulated miRNAs are genes linked to autism such as neurexin and SHANK3 that, as mentioned above, code for crucial synaptic proteins. Because of these results, the authors further emphasize that autism is not a single disorder, "While this idea is now fully accepted clinically and is reflected in the nomenclature when we speak of 'autism spectrum disorders' there remains some reluctance to adopt the view that autism is also genetically diverse. Many studies lump together all cases and then search for a common genetic signature. However, recent papers have revealed different rare mutations among small numbers of autism patients, and hence, suggest that autism may be even more genetically diverse than it is clinically diverse. Using a unique type of genetic signature related to the expression of a special class of genes called microRNAs we have shown the very broad underlying diversity of the condition we call autism." Future work by this team will now involve comparison of different brain areas for miRNA expression.

Worth mentioning, as a final note, is yet another mitochondrial function which may be pertinent in autism. The oxygen needed for mitochondrial energy (ATP) production has to be carefully managed by the cell since reactive oxygen species (ROS) such as free radicals and peroxides derived from oxygen metabolism can damage cell components. Oxidative stress (OS) is the steady state level of oxidative damage in tissues, and a number of molecules (like vitamins and other antioxidants) are known to regulate the process and guard against damage. Dysregulation of these cellular safeguards can occur by endogenous (nitric oxide) or exogenous (valproic acid, viral infections) factors. The links between oxidative stress, mitochondrial dysfunction and autism were reviewed in a previous article -- read more about these topics here.


Acknowledgement

We wish to recognize the gifts of hope by the families of brain donors. Autism Speaks' Autism Tissue Program supports specialized neuropathology research by providing approved scientists access to the most rare and necessary of resources, post mortem human brain tissue. Anyone can register to be a future brain tissue donor. Information can be found at www.autismtissueprogram.org or call toll-free (877) 333-0999 for a packet of information, with questions or to initiate a brain donation.

References

1. Lepagnol-Bestel AM, Maussion G, Boda B, Cardona A, Iwayama Y, Delezoide AL, Moalic JM, Muller D, Dean B, Yoshikawa T, Gorwood P, Buxbaum JD, Ramoz N, Simonneau M. 2008. SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects. Molecular Psychiatry. 2008 13(4):385-97.


2. Maussion G, Carayol j, Lepagnol-Bestel A-M, Tores F, Loe-Mie T, Milbreta U, Rousseau F, Fontaine K, Renaud J, Moalic J-M, Philippi A, Chedotal A, Gorwood P, Ramoz N, Hager j and Michel Simonneau. 2008. Convergent evidence identifying MAP/microtubule affinity regulating kinase 1 (MARK1) as a susceptibility gene for autism. Human Molecular Genetics. 17:1-11


3. Kawther Abu-Elneel, Tsunglin Liu, Francesca S Gazzaniga, Yuhei Nishimura,
Dennis P Wall, Daniel H Geschwind, Kaiqin Lao, Kenneth S Kosik. 2008. Heterogeneous Dysregulation of microRNAs across the Autism Spectrum. Neurogenetics. 9:153-161.