Research brings hope for new treatments for spinal muscular atrophy, autism

Ancient bacteria that have evolved to become integral to our cells – converting nutrients from food into energy – may also contribute to neurologic disorders, such as spinal muscular atrophy (SMA) and autism, according to research in the lab of Yongchao Ma, PhD, from Ann & Robert H. Lurie Children’s Hospital of Chicago.

Called mitochondria, these mysterious parts of the cell even have retained their own DNA. Traditionally they are known as the “powerhouse of the cell.” In recent years, however, mitochondria have been recognized as regulating many functions, including gene expression and how cells communicate. Dr. Ma’s research focuses on how dysregulation by mitochondria may lead to motor neuron degeneration in SMA or improper neuron connections in autism.

“Our lab has been investigating the mechanisms by which mitochondria influences development of neurologic diseases in order to discover new targets for treatment,” said Dr. Ma, a neurobiologist at Stanley Manne Children’s Research Institute at Lurie Children’s and Associate Professor of Pediatrics, Neurology and Neuroscience at Northwestern University Feinberg School of Medicine.

Dr. Ma and his team found that a protein called Fascin, which is widely studied in cancer, surprisingly regulates mitochondria. When Fascin activity goes awry, it causes abnormal mitochondria division and their DNA to leak out. This triggers inflammation, which contributes to motor neuron degeneration, as is the case with SMA.

SMA is a genetic disease that disrupts the nerve cells that control voluntary muscle movement. Symptoms of motor neuron degeneration could start at as early as 3 months of age and lead to muscle atrophy, paralysis and death, often before the child’s second birthday.

“Gene therapy and antisense oligonucleotide have revolutionized SMA treatment, but they only work for a subgroup of patients and can be too toxic,” said Dr. Ma. “We are hoping our research will lead to an alternative therapy that will be safe and effective for all children with SMA, and can be used in combination with other treatments.”

Autism, of course, is very different from SMA, but Dr. Ma and colleagues found that mitochondria also play an important role in its development.

The mechanism that Dr. Ma studies involves metabolites of mitochondria, or substances that are formed when mitochondria generate energy through a molecule called ATP. These metabolites regulate gene expression and stem cell proliferation in the brain. Errors within this process result in either not enough neurons, or the timing in neuron development might be off. This creates atypical brain connections, which affect how different parts of the brain communicate and process information, possibly leading to symptoms of autism such as social and communication difficulties, cognitive differences and sensory sensitivities.

“We have much to learn about these complex disorders, and research into mitochondrial functions provides a fascinating and promising direction,” said Dr. Ma. “Our work brings hope for new treatments for conditions like SMA and autism that begin in childhood, and it is also relevant to diseases in older populations, including Alzheimer’s and Parkinson’s.”

Dr. Ma holds the Children’s Research Fund Endowed Professorship in Neurobiology at Lurie Children’s.