SMN loss seen to affect key brain signaling molecule, norepinephrine
Study into how protein's deficiency influences SMA beyond motor neurons
Disruptions to norepinephrine (NE), a brain signaling molecule, appear to be due to SMN protein loss and could contribute to disease progression in spinal muscular atrophy (SMA) patients, according to recent research.
Levels of the molecule, as well as the enzymes needed to produce it, were deficient in a mouse model of SMA. And in the spinal fluid of patients with SMA type 1, treatment with Spinraza (nusinersen) was found to lead to significant increases in norepinephrine levels.
Metabolic analyses indicated signs of disrupted cellular energy and amino acid metabolism. These amino acids, the building blocks of proteins, are critical for building NE and related signaling molecules, called neurotransmitters.
These findings “pave the way for novel therapeutic strategies targeting cerebral NE metabolism and nutritional approaches with selective amino acid supplementation as an add-on to the current SMA therapies,” the researchers wrote.
The study, “SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy,” was published in Communications Biology.
SMN protein deficiency known to affect more than motor neuron health
The most common forms of SMA are caused by mutations in the SMN1 gene, leading to a lack of the SMN protein. The best studied effect of this SMN loss is the degeneration of motor neurons — nerve cells that communicate with muscles to coordinate voluntary movements — leading to the disease’s cardinal symptoms of progressive muscle weakness and wasting.
But the SMN protein influences a wide range of cellular functions, and its loss could cause biochemical disruptions throughout the body beyond that of motor neuron degradation.
Metabolic dysfunction across organs has been observed in SMA patients, but these alterations have been given less attention. It is not clear when these changes arise, or whether they are a direct consequence of SMN loss or secondary to motor neuron degeneration.
Moreover, while brain development is known to be affected in SMA, the specific biochemical pathways involved “remain poorly characterized,” wrote the researchers, all with various institutions in Italy.
In a 2022 published study, these scientists found evidence of changes in certain metabolic pathways, namely those associated with energy production and amino acid metabolism, in the cerebrospinal fluid (CSF) of SMA patients being treated with Spinraza. This finding could represent important biochemical pathways in SMA. (Of note, the CSF is the fluid that surrounds the brain and spinal cord.)
Particularly altered were certain amino acids that serve as precursors for the production of neurotransmitters.
Now these researchers explored whether such metabolic changes might be observed in an SMA mouse model and, if so, when they arise.
Low levels of norepinephrine seen in brains of SMA mouse model
They observed that SMA mice had significant metabolic abnormalities in the liver and brain relative to healthy mice, particularly with molecules related to energy production. Notably, these changes in the liver could be observed very early in the disease’s course, but were only observed in the brain at later symptomatic stages.
“Our findings … align with previous clinical and preclinical results indicating severe energy failure … in SMA,” the researchers noted.
In the brain, evidence of perturbed amino acid metabolism also was observed, prompting the researchers to look at levels of a family of neurotransmitters called catecholamines, which includes norepinephrine.
The brains of SMA mice exhibited a “remarkable” reduction in NE at both early and late disease stages, the scientists found, with a similar, but smaller, reduction observed in the animals’ spinal cord.
Consistently, significant alterations were seen in the levels of enzymes needed to produce catecholamines, including reductions in certain ones important for generating NE.
In line with that finding, the activity of genes responsible for producing norepinephrine enzymes was altered. Such alterations were not observed in mouse models of other motor neuron diseases, indicating that these enzyme abnormalities arise from “SMN deficiency rather than being a non-specific effect due to motor neuron degeneration,” the team noted.
Similar changes related to energy and amino acid metabolism also were observed in the CSF of three untreated infants with SMA type 1 relative to healthy children.
Spinraza raises norepinephrine levels in CSF of SMA type 1 patients
Next, the researchers looked at 33 SMA patients being treated with Spinraza at a Rome hospital. They found a statistically significant increase in norepinephrine levels in the CSF of those with SMA type 1 at two and 10 months after starting treatment, compared with pretreatment levels. These changes in NE levels, however, were not associated with changes in motor performance.
No increases in NE were observed in patients with milder forms of SMA, namely type 2 or type 3.
“Considering the critical role of NE signaling in controlling neuronal excitability and energy metabolism,” the researchers wrote, “we propose that dysfunctional NE neurotransmission might represent a novel unrecognized primary factor contributing to the disease progression events associated with SMN deficiency.”
Given its known role in energy metabolism, norepinephrine might offer a link between SMN levels and disturbed energy production in SMA, they added.
While further studies are needed in larger SMA patient groups, “our results provide a milestone advance for understanding the regulatory role of SMN on neurotransmission and the beneficial effects of SMN-inducing therapies at a neurochemical level,” the team concluded.
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