L-type amino acid transporter 1 (LAT1, encoded by Slc7a5) contributes to amino acid homeostasis and signaling in numerous cell types. Several lines of evidence implicate LAT1 in mammalian central nervous system development, but its functional significance in specific neuronal subtypes is largely unknown. Here, we demonstrate that LAT1/Slc7a5 expression in synapsin 1 (Syn1)-expressing neurons is essential for motor circuit development and motor coordination at the perinatal stage. Mice lacking Slc7a5 in Syn1-expressing neurons exhibited progressive motor coordination deficits and early postnatal lethality. These deficits were associated with selective degeneration of lower spinal motor neurons, reactive gliosis, skeletal muscle atrophy, and maldevelopment of neuromuscular junctions (NMJs), but no abnormalities in gross brain structure or neuronal viability. Pharmacological inhibition of apoptosis prolonged the survival of Slc7a5-deficient mice and reduced both lower motor neuron loss and NMJ maldevelopment. Furthermore, multi-cohort transcriptome analyses revealed inactivation of amino acid transport activity along with the downregulation of Slc7a5 expression in motor neurons of spinal muscular atrophy model mice. These results suggest that the amino acid transport system is essential for the survival and function of lower spinal motor neurons during early postnatal development, and identifies LAT1 as a potential therapeutic target for early-onset motor neuron diseases.

Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder caused by deletions or mutations in the SMN1 gene, leading to reduced levels of the survival motor neuron (SMN) protein. Gene therapy using adeno-associated virus serotype 9 (AAV9) has emerged as a promising treatment strategy for SMA by enabling systemic delivery of a functional SMN1 gene. This preclinical study evaluates the long-term safety and efficacy of an AAV9 vector expressing a codon-optimized human SMN1 gene (AAV9-hcoSMN) in neonatal mice. A single intravenous dose of 5 × 1011 vector genomes per mouse was administered, with animals monitored over a 24-week period for therapeutic outcomes and safety profiles. Safety assessments, including clinical observations, haematological and biochemical analyses (such as CBC, liver function tests and coagulation tests), necropsy and histopathological examinations via H&E, revealed no significant adverse effects. Treated mice demonstrated 100% survival rates and exhibited no abnormalities in organ structure or function compared to controls. Efficacy assessments using quantitative PCR confirmed robust SMN1 transgene expression in key tissues, including the central nervous system, heart, liver and skeletal muscles. These findings demonstrate that AAV9-hcoSMN therapy achieves sustained and widespread transgene expression with no observable toxicity in a neonatal mouse model, reinforcing the therapeutic potential of AAV9-based gene delivery for SMA. By providing robust preclinical evidence of both safety and efficacy, this study contributes to the growing body of data supporting gene therapy as a viable, long-term treatment strategy for SMA. These results also help inform vector design, dosing strategies and safety monitoring for future clinical translation. Further studies in larger animal models are warranted to assess long-term durability and immunogenicity prior to human application. SUMMARY: Spinal muscular atrophy (SMA) is a serious genetic disorder that weakens muscles and can be life-threatening. Our study tested a potential gene therapy using a harmless virus (AAV9) to deliver a healthy version of the faulty gene that causes SMA. We treated newborn mice and observed them for 6 months to check for any side effects and see if the therapy worked. The results were promising-treated mice had no health problems, and the new gene was active in important organs like the brain, muscles, and heart. This research brings us closer to a safe and effective treatment for SMA.

Spinal muscular atrophy (SMA) is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. While traditionally viewed as a motor neuron disorder, there is involvement of various peripheral organs in SMA. Notably, fatty liver has been observed in SMA mouse models and SMA patients. Nevertheless, it remains unclear whether intrinsic depletion of SMN protein in the liver contributes to pathology in the peripheral or central nervous systems. To address this, we developed a mouse model with a liver-specific depletion of SMN by utilizing an Alb-Cre transgene together with one Smn2B allele and one Smn1 exon 7 allele flanked by loxP sites. Initially, we evaluated phenotypic changes in these mice at postnatal day 19 (P19), when the severe model of SMA, the Smn2B/- mice, exhibit many symptoms of the disease. The liver-specific SMN depletion does not induce motor neuron death, neuromuscular pathology or muscle atrophy, characteristics typically observed in the Smn2B/- mouse at P19. However, mild liver steatosis was observed, although no changes in liver function were detected. Notably, pancreatic alterations resembled that of Smn2B/-mice, with a decrease in insulin-producing β-cells and an increase in glucagon-producingα-cells, accompanied by a reduction in blood glucose and an increase in plasma glucagon and glucagon-like peptide (GLP-1). These changes were transient, as mice at P60 exhibited recovery of liver and pancreatic function. While the mosaic pattern of the Cre-mediated excision precludes definitive conclusions regarding the contribution of liver-specific SMN depletion to overall tissue pathology, our findings highlight an intricate connection between liver function and pancreatic abnormalities in SMA.

Spinal muscular atrophy (SMA) is caused by reduced expression of survival motor neuron (SMN) protein. Previous studies indicated SMA causes not only lower motor neuron degeneration but also extensive brain involvement. This study aimed to investigate the changes of brain white matter and structural network using diffusion tensor imaging (DTI) in children with type 2 and 3 SMA. Forty-two type 2 and 3 pediatric SMA patients and 42 age- and gender-matched healthy controls (HC) were prospectively enrolled in this study. The tract-based spatial statistics (TBSS) was used to assess white matter integrity and the structural network properties were calculated based on DTI white matter fiber tracking and the graph theory approach. A partial correlation was performed to explore the relationship between white matter parameters and clinical characteristics. In total, 42 patients (mean age, 10.86 ± 4.07 years; 23 men) were included. TBSS analysis revealed widespread white matter changes in SMA patients. The SMA patients showed changes in multiple small-world and network efficiency parameters. Compared to the HC group, SMA showed increased characteristic path length (Lp), normalized clustering coefficient (γ), small-world characteristic (σ), and decreased global efficiency (Eglob) (all p < 0.05). In the node properties, right supramarginal gyrus, right orbital part of superior frontal gyrus, right supplementary motor area, and left median cingulate and paracingulate gyri changed in SMA patients. A decreased axial diffusivity (AD) value was associated with lower Hammersmith Functional Motor Scale-Expanded scores (r = 0.45, p = 0.02), which means that the symptoms of SMA patients are more severe. This study found white matter and DTI-based brain network abnormalities in SMA patients, suggesting SMN protein deficiency may affect white matter development.

This study investigated the changes in brain gray and white matter structure in SMA patients and their correlation with the severity of the disease. A total of 43 SMA patients (including 22 type II and 21 type III SMA patients) and 37 healthy controls were evaluated by MRI. The gray matter volume, gray matter thickness, gray matter surface area, and white matter volume of designated brain regions automatically segmented by FreeSurfer, were compared. We evaluate clinical characteristics of SMA and study the correlation between clinical characteristics and structural changes. SMA showed significant bilateral cortical superficial area loss in the frontal, parietal, and temporal lobes and global white matter volume decreases. Moreover, these patients were also found with an increased mean thickness of entire brain and right gray matter. An increased right postcentral gyrus superficial area, right central sulcus volume, and white matter volume of the right postcentral were associated with higher HFMSE scores. Type 2 and 3 children SMA had extensive, multifocal, symmetrical gray and white matter alterations. Postcentral gyrus degeneration of SMA was associated with the severity of muscular atrophy. The lack of SMN protein possibly interacted with cerebellar structural changes in somatosensory areas. • MRI has found brain changes in SMA patients, however, there is no unified conclusion and lack of correlation with clinical degree in children SMA with type 2-3. • Type II and II children SMA had extensive, multifocal, symmetrical gray and white matter alterations. Postcentral gyrus degeneration of SMA was associated with the severity of muscular atrophy. Cerebellar structural changes in somatosensory areas may attribute to the lack of SMN protein.