Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

Simone, Carla; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy J.; Papadimitriou, Dimitra; Ré, Diane B.; Corti, Stefania

doi:10.1007/s00018-015-2106-9

Cited by 54 publications

(53 citation statements)

References 149 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…SMA is increasingly described as a disease affecting tissues and cell types beyond the motor neuron, suggesting that effective disease intervention may require body-wide correction of SMN protein levels to achieve a complete reversal or amelioration of the disease state. [5][6][7] This is consistent with the requirement of peripheral SMN restoration for long-term rescue in a severe SMA animal model. [8][9][10] SMN protein is ubiquitously expressed throughout the body and is implicated in several basic cellular functions.…”

Section: Introductionsupporting

confidence: 81%

“…Accumulating evidence challenges the idea that SMA is solely a disease of motor neurons. SMA is increasingly described as a disease affecting tissues and cell types beyond the motor neuron, suggesting that effective disease intervention may require body‐wide correction of SMN protein levels to achieve a complete reversal or amelioration of the disease state . This is consistent with the requirement of peripheral SMN restoration for long‐term rescue in a severe SMA animal model …”

Section: Introductionsupporting

confidence: 61%

“…SMN protein is ubiquitously expressed throughout the body and is implicated in several basic cellular functions . SMN protein may have a role in many cells and tissues, such as skeletal muscle, heart, bone, and autonomic and nervous systems; and deficiencies may contribute to the disease state …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs

Poirier

Weetall

Heinig

et al. 2018

Pharmacology Res & Perspec

131

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene. A second gene, SMN2, produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1. Risdiplam (RG7916; RO7034067) is an orally administered, small‐molecule SMN2 pre‐mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n = 90), rats (n = 148), and monkeys (n = 24). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39 weeks. A parallel dose‐dependent increase in SMN protein levels was seen in CNS and peripheral tissues in two SMA mouse models dosed with risdiplam. These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients’ blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues.

show abstract

Section: Introductionsupporting

confidence: 81%

Section: Introductionsupporting

confidence: 61%

See 1 more Smart Citation

Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs

Poirier

Weetall

Heinig

et al. 2018

Pharmacology Res & Perspec

131

View full text Add to dashboard Cite

show abstract

“…This has prompted much inquiry into why MNs are seemingly more susceptible than other cells to low SMN levels (Kolb et al 2007;Simone et al 2016;Tu et al 2017).…”

Section: Spinal Muscular Atrophy (Sma)mentioning

confidence: 99%

“…SMA is classified into three types based on age of onset and disease severity (Simone et al 2016). The different clinical manifestations reflect the overall amounts of SMN protein (Lefebvre et al 1997), which are determined by the mutation (deletion vs. partial LOF) in SMN1 (Tu et al 2017), SMN2 gene copy number (Taylor et al 1998;Harada et al 2002), and the amount of full-length SMN2 produced (Fig.…”

Section: Spinal Muscular Atrophy (Sma)mentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

View full text Add to dashboard Cite

Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.

show abstract

Survival motor neuron protein deficiency alters microglia reactivity

Khayrullina

Alipio‐Gloria

Deguise

et al. 2022

Glia

View full text Add to dashboard Cite

Survival motor neuron (SMN) protein deficiency results in loss of alpha motor neurons and subsequent muscle atrophy in patients with spinal muscular atrophy (SMA). Reactive microglia have been reported in SMA mice and depleting microglia rescues the number of proprioceptive synapses, suggesting a role in SMA pathology. Here, we explore the contribution of lymphocytes on microglia reactivity in SMA mice and investigate how SMN deficiency alters the reactive profile of human induced pluripotent stem cell (iPSC)‐derived microglia. We show that microglia adopt a reactive morphology in spinal cords of SMA mice. Ablating lymphocytes did not alter the reactive morphology of SMA microglia and did not improve the survival or motor function of SMA mice, indicating limited impact of peripheral immune cells on the SMA phenotype. We found iPSC‐derived SMA microglia adopted an amoeboid morphology and displayed a reactive transcriptome profile, increased cell migration, and enhanced phagocytic activity. Importantly, cell morphology and electrophysiological properties of motor neurons were altered when they were incubated with conditioned media from SMA microglia. Together, these data reveal that SMN‐deficient microglia adopt a reactive profile and exhibit an exaggerated inflammatory response with potential impact on SMA neuropathology.

show abstract

Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

Cited by 54 publications

References 149 publications

Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs

Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

Survival motor neuron protein deficiency alters microglia reactivity

Contact Info

Product

Resources

About