A study of tuberous sclerosis, a syndrome associated with autism, suggests a new treatment approach that could extend to other forms of autism.
The genetic disorder tuberous sclerosis complex (TSC) causes autism in about half of the children affected. Because its genetics are well defined, TSC offers a window into the cellular and network-level perturbations in the brain that lead to autism. A study published today by Cell Reports cracks the window open further, in an intriguing new way. It documents a defect in a basic housekeeping system cells use to recycle and renew their mitochondria.
Mitochondria are the organelles responsible for energy production and metabolism in cells. As they age or get damaged, cells digest them through a process known as autophagy (“self-eating”), clearing the way for healthy replacements. (Just this month, research on autophagy earned the Nobel Prize in Physiology or Medicine.)
Mustafa Sahin, MD, PhD, Darius Ebrahimi-Fakhari, MD, PhD, and Afshin Saffari, in Boston Children’s Hospital’s F.M. Kirby Neurobiology Center now report that autophagy goes awry in brain cells affected by TSC. But they also found that two existing medications restored autophagy: the epilepsy drug carbamazepine and drugs known as mTOR inhibitors. The findings may hold relevance not just for TSC but possibly for other forms of autism and some other neurologic disorders.
Out with the old mitochondria, in with the new mitochondria
Defects in mitophagy (autophagy of mitochondria) have already been implicated in such disorders as Parkinson’s disease and Alzheimer’s disease. Mitochondria have also been studied in autism for years, but the findings have been largely anecdotal and inconclusive. In part, this is because the autism population is diverse and hard to define.
“We decided to use tuberous sclerosis, a genetically defined disorder that has a high incidence of autism, as a model to understand the role of mitochondrial dynamics,” says Sahin, director of the Translational Neuroscience Center at Boston Children’s and the study’s senior investigator. “Our findings point to possible treatments for enhancing mitophagy for some neurodevelopmental and neurodegenerative diseases.”
Sahin and colleagues studied both rat neurons affected by TSC and neurons derived from TSC patients, made from induced pluripotent stem cells, or iPSCs. Using live-cell imaging, they examined the distribution and dynamics of mitochondria. The TSC neurons as a whole had more mitochondria, and in particular more fragmented and dysfunctional mitochondria.
Axons take the hit
The researchers then examined the neurons’ axons, the projections that send messages to other cells. Mitochondria play a critical role in axons, and cluster in high numbers at presynaptic sites — the tips of axons that form synapses or junctions with other neurons and release neurotransmitters.
The axons of both rat neurons and neurons from TSC patients were depleted of mitochondria.
“We think this could have implications for how neurons talk to each other,” says Ebrahimi-Fakhari, a resident at Boston Children’s who co-led the study with medical student Afshin Saffari. “Synapses that lose the support of mitochondria might be releasing neurotransmitters too much or too little.”
The team dove deeper and found that while mitophagy was increased in the body of the cell, it was reduced in the axons. Proteins involved in the early steps of mitophagy increased in the axons, but the autophagosomes and lysosomes that do the actual digesting didn’t appear around the damaged mitochondria. Instead, the mitochondria were being shuttled out of the axons back to the body of the cell, without being replaced.
Therapeutic opportunity for TSC and autism?
The researchers were able to restore normal mitophagy — in both neurons in a dish and in live mice — in several ways:
- by reintroducing a healthy copy of the gene mutated in TSC
- by adding rapamycin (an mTOR inhibitor that the Sahin lab has shown to improve TSC in animal models, and that is currently in clinical trials)
- with carbamazepine, a common anti-seizure medication that enhances autophagy through a different mechanism than mTOR inhibitors.
Once treated, the formerly dysfunctional neurons were able to clear their damaged mitochondria and replenish functioning mitochondria. The change was most notable at presynaptic sites where mitochondria are most critical.
The findings shed intriguing light on what scientists already know about TSC and autism. Growing evidence from the Sahin lab and elsewhere has tied autism, intellectual disability and seizures in patients with TSC to dysfunction in synapses. Autism itself is increasingly seen as a synapse disorder, and this study hints at one possible way synapses might go awry.
“Our work defines mitochondrial homeostasis as a therapeutic target for TSC, and may also have implications for other neurological diseases that involve mitochondrial dysfunction,” says Ebrahimi-Fakhari.
Ebrahimi-Fakhari and Saffari are also affiliated with University Hospital Heidelberg, Germany. The study was supported by the Graduate Academy and the Young Investigator Award Program at Heidelberg University, the Daimler & Benz Foundation, the Reinhard-Frank Foundation, the German National Academic Foundation, the Nancy Lurie Marks Family Foundation and the Boston Children’s Hospital Translational Research Program. Co-authors Christopher Conrad and Jonathan M. Rothberg are employees of LAM Therapeutics.