Hassan Amber, di Vito Raffaella, Nuzzo Tommaso, Vidali Matteo, Carlini Maria Jose, Yadav Shubhi, Yang Hua, D'Amico Adele, Kolici Xhesika, Valsecchi Valeria, Panicucci Chiara, Pignataro Giuseppe, Bruno Claudio, Bertini Enrico, Errico Francesco, Pellizzoni Livio, Usiello Alessandro
Laboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate, 80145, Naples, Italy.
European School of Molecular medicine, University of Milan, Milan, Italy.
bioRxiv. 2024 Oct 22:2024.10.22.619645. doi: 10.1101/2024.10.22.619645.
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to motor neuron survival, SMN deficiency affects the integrity and function of afferent synapses that provide glutamatergic excitatory drive essential for motor neuron firing and muscle contraction. However, it is unknown whether deficits in the metabolism of excitatory amino acids and their precursors contribute to neuronal dysfunction in SMA. To address this issue, we measured the levels of the main neuroactive D- and L-amino acids acting on glutamatergic receptors in the central nervous system of SMNΔ7 mice as well as the cerebrospinal fluid (CSF) of SMA patients of varying severity before and after treatment with the SMN-inducing drug Nusinersen. Our findings reveal that SMN deficiency disrupts glutamate and serine metabolism in the CSF of severe SMA patients, including decreased concentration of L-glutamate, which is partially corrected by Nusinersen therapy. Moreover, we identify dysregulated L-glutamine to L-glutamate conversion as a shared neurochemical signature of altered glutamatergic synapse metabolism that implicates astrocyte dysfunction in both severe SMA patients and mouse models. Lastly, consistent with a correlation of higher CSF levels of D-serine with better motor function in severe SMA patients, we show that daily supplementation with the NMDA receptor co-agonist D-serine improves neurological deficits in SMNΔ7 mice. Altogether, these findings provide direct evidence for dysregulation of D- and L-amino acid metabolism linked to glutamatergic neurotransmission in severe SMA and have potential implications for treating this neurological disorder.
脊髓性肌萎缩症（SMA）是一种神经肌肉疾病，由存活运动神经元（SMN）蛋白表达减少引起。除了运动神经元存活外，SMN缺乏还会影响传入突触的完整性和功能，这些突触提供了运动神经元放电和肌肉收缩所必需的谷氨酸能兴奋性驱动。然而，尚不清楚兴奋性氨基酸及其前体的代谢缺陷是否导致SMA中的神经元功能障碍。为了解决这个问题，我们测量了SMNΔ7小鼠中枢神经系统中作用于谷氨酸能受体的主要神经活性D-和L-氨基酸水平，以及不同严重程度的SMA患者在使用诱导SMN的药物诺西那生治疗前后的脑脊液（CSF）水平。我们的研究结果表明，SMN缺乏会破坏严重SMA患者脑脊液中的谷氨酸和丝氨酸代谢，包括L-谷氨酸浓度降低，诺西那生治疗可部分纠正这一情况。此外，我们发现L-谷氨酰胺向L-谷氨酸的转化失调是谷氨酸能突触代谢改变的共同神经化学特征，这意味着严重SMA患者和小鼠模型中星形胶质细胞功能障碍。最后，与严重SMA患者脑脊液中较高的D-丝氨酸水平与更好的运动功能相关一致，我们表明每天补充NMDA受体共激动剂D-丝氨酸可改善SMNΔ7小鼠的神经功能缺损。总之，这些发现为严重SMA中与谷氨酸能神经传递相关的D-和L-氨基酸代谢失调提供了直接证据，并对治疗这种神经系统疾病具有潜在意义。
