Amino acid balance could play role in SMA, study finds
Neuroactive amino acid imbalances found in SMA patients, mice

The balance of amino acids capable of influencing neurological function is disrupted in patients with spinal muscular atrophy (SMA) and in mouse models, a study found.
Observed changes in patients were partially normalized after treatment with the disease-modifying therapy Spinraza (nusinersen). Treatment with one of the amino acids, D-serine, improved motor function in a mouse model.
Taken together, the findings offer “direct evidence” of amino acid dysregulation in SMA, and “have potential implications for treating this neurological disorder,” the researchers wrote. The study, “Dysregulated balance of D- and L-amino acids modulating glutamatergic neurotransmission in severe spinal muscular atrophy,” was published in Neurobiology of Disease.
In SMA, genetic mutations lead to a lack of the SMN protein, which causes progressive degeneration of the specialized nerve cells that control voluntary movements, or motor neurons. Patients experience muscle weakness, among other SMA symptoms.
Problems within individual motor neurons can’t fully explain how SMA manifests, according to the authors. Rather, they said, research suggests that impaired communication between nerve cells may disrupt larger neuronal circuits involved in motor control.
Amino acid balance
One thing that’s observed in SMA is a loss of excitatory input (activating signals) to motor neurons from the sensory nerve cells that communicate with them.
Normally, these sensory cells release a signaling chemical called glutamate at synapses, the sites through which nerve cells communicate, which in turn activates motor neurons. Without this input, motor neurons don’t fire as they should, and the ability for muscles to contract is impaired.
Glutamate is an amino acid, one of the building blocks of proteins. While it is a key player, there are other neuroactive amino acids that can directly or indirectly influence function of the same synapses. These include serine and aspartate, as well as the glutamate precursor glutamine.
Whether these amino acids contribute to neuronal dysfunction in SMA hasn’t been explored. In the study, researchers measured their levels in the cerebrospinal fluid (the fluid surrounding spinal cord and brain) of untreated SMA patients — 34 with SMA type 1, 22 with SMA type 2, and 17 with SMA type 3 — and in seven healthy people, who served as a control group.
Results showed a variety of amino acid alterations in the SMA patients. Among the observed changes was a glutamate deficiency in people with SMA type 1, as well as an elevated glutamine-to-glutamate ratio in SMA types 1 and 2 relative to healthy people, reflective of impaired glutamine to glutamate conversion.
Amino acid alterations in SMA type 1 patients were found to be partially corrected 302 days (about 10 months) after starting treatment with Spinraza for a subgroup of patients with available samples. In people with SMA type 3, Spinraza was associated with decreases in levels of a number of amino acids, with no effects in SMA type 2.
“Disease severity and the stage of SMA progression appear to be critical factors guiding specific metabolic responses to [Spinraza] treatment,” the researchers wrote.
The scientists also looked at levels of amino acids in a mouse model of SMA. Results showed altered metabolism of neuroactive amino acids during symptomatic stages, particularly an increased glutamine-to-glutamate ratio, relative to healthy mice.
This altered glutamine-to-glutamate conversion “emerges as a conserved signature of neurochemical dysregulation in … severe SMA patients and … mouse models,” the researchers wrote.
Certain serine alterations were observed in SMA type 1 patients. In these patients, serine measures correlated with motor function both before and after treatment, though the relationship appeared dependent on age. In those with SMA type 2, serine levels positively correlated with motor function after Spinraza initiation.
Given the potential relationship between serine and motor function, the researchers treated the SMA mouse model with D-serine supplements. This led to a moderate improvement in motor function, but did not influence weight, survival, or SMN levels.
Although it isn’t exactly clear how D-serine influences neurological function, the findings “highlight the potential of this atypical amino acid as a therapeutic target and encourage exploration of combinatory therapeutic strategies in future clinical trials,” the researchers wrote.
Overall, the study demonstrated “prominent dysregulation” of amino acids that influence glutamatergic synapses, and “supports further investigation into pharmacological approaches … aimed at improving glutamatergic neurotransmission [chemical communication] deficits for use in combination therapies,” the team concluded.