Metabolic Dysfunction in Spinal Muscular Atrophy

Deguise, Marc-Olivier; Chehadé, Lucia; Kothary, Rashmi

doi:10.3390/ijms22115913

Cited by 19 publications

(13 citation statements)

References 256 publications

(482 reference statements)

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“…The cell division pathway and axon guidance genes were significantly downregulated in the P5 spinal cord, which was not observed in the P4, indicating that SMA pathogenesis undergoes great physiopathological changes from the middle stage to the late stage [ 22 ]. Most of the down-regulated pathways in the P4 spinal cord are metabolically related, consistent with the widespread metabolic dysregulation observed in SMA that has been demonstrated [ 66 ].…”

Section: Discussionsupporting

confidence: 78%

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

et al. 2022

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Although spinal muscular atrophy (SMA) is a motor neuron disease caused by the loss of survival of motor neuron (SMN) proteins, there is growing evidence that non-neuronal cells play important roles in SMA pathogenesis. However, transcriptome alterations occurring at the single-cell level in SMA spinal cord remain unknown, preventing us from fully comprehending the role of specific cells. Here, we performed single-cell RNA sequencing of the spinal cord of a severe SMA mouse model, and identified ten cell types as well as their differentially expressed genes. Using CellChat, we found that cellular communication between different cell types in the spinal cord of SMA mice was significantly reduced. A dimensionality reduction analysis revealed 29 cell subtypes and their differentially expressed gene. A subpopulation of vascular fibroblasts showed the most significant change in the SMA spinal cord at the single-cell level. This subpopulation was drastically reduced, possibly causing vascular defects and resulting in widespread protein synthesis and energy metabolism reductions in SMA mice. This study reveals for the first time a single-cell atlas of the spinal cord of mice with severe SMA, and sheds new light on the pathogenesis of SMA.

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Section: Discussionsupporting

confidence: 78%

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

et al. 2022

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“…Spinal muscular atrophy (SMA) affects lower motor neurons and is caused by mutations to the gene survival motor neuron 1. In SMA, there is widespread metabolic dysfunction, impacting glucose, amino acid, and lipid metabolism [168]. In a mouse model of SMA where a drug treatment was paired with nutritional support, SMA mice had increased survival and enhanced skeletal muscle innervation.…”

Section: Other Motor Neuron Diseasesmentioning

confidence: 99%

NAD+ Metabolism and Diseases with Motor Dysfunction

Lundt

Ding

2021

Genes

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Neurodegenerative diseases result in the progressive deterioration of the nervous system, with motor and cognitive impairments being the two most observable problems. Motor dysfunction could be caused by motor neuron diseases (MNDs) characterized by the loss of motor neurons, such as amyotrophic lateral sclerosis and Charcot–Marie–Tooth disease, or other neurodegenerative diseases with the destruction of brain areas that affect movement, such as Parkinson’s disease and Huntington’s disease. Nicotinamide adenine dinucleotide (NAD+) is one of the most abundant metabolites in the human body and is involved with numerous cellular processes, including energy metabolism, circadian clock, and DNA repair. NAD+ can be reversibly oxidized-reduced or directly consumed by NAD+-dependent proteins. NAD+ is synthesized in cells via three different paths: the de novo, Preiss–Handler, or NAD+ salvage pathways, with the salvage pathway being the primary producer of NAD+ in mammalian cells. NAD+ metabolism is being investigated for a role in the development of neurodegenerative diseases. In this review, we discuss cellular NAD+ homeostasis, looking at NAD+ biosynthesis and consumption, with a focus on the NAD+ salvage pathway. Then, we examine the research, including human clinical trials, focused on the involvement of NAD+ in MNDs and other neurodegenerative diseases with motor dysfunction.

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“…The cell division pathway and axon guidance genes were significantly downregulated in the P5 spinal cord, which was not observed in the P4, indicating that SMA pathogenesis undergoes great physiopathological changes from the middle stage to the late stage [22]. Most of the down-regulated pathways in the P4 spinal cord are metabolically related, consistent with the widespread metabolic dysregulation of SMA that has been demonstrated [64].…”

Section: Discussionmentioning

confidence: 74%

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

Sun

Qiu

Yang

et al. 2022

Preprint

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Although spinal muscular atrophy (SMA) is a motor neuron disease caused by the loss of survival of motor neuron proteins, there is growing evidence that lesions in nonmotor neuron cells are involved in SMA pathogenesis. Transcriptome alterations occurring at the single-cell level in SMA spinal cord are unknown. Here, we performed single-cell RNA sequencing of the spinal cord of a severe SMA mouse model, and characterized ten cell types as well as their differentially expressed genes. Using CellChat, we found that cellular communication between different cell types in the spinal cord of SMA mice is substantially reduced. A dimensionality reduction analysis revealed 29 cell subtypes and differentially expressed genes for each subtype. Among them, the most significant change in the SMA spinal cord at the single-cell level was observed in a subpopulation of vascular fibroblasts. This subpopulation was greatly reduced, which may be responsible for vascular defects in SMA mice and may lead to widespread reductions in protein synthesis and energy metabolism. This study is the first to report a single-cell atlas of the spinal cord of mice with severe SMA, providing new insights into SMA pathogenesis.

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Metabolic Dysfunction in Spinal Muscular Atrophy

Cited by 19 publications

References 256 publications

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

NAD+ Metabolism and Diseases with Motor Dysfunction

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

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