Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensorimotor circuit

Alstyne, Meaghan Van; Tattoli, Ivan; Delestrée, Nicolas; Recinos, Yocelyn; Workman, Eileen; Shihabuddin, Lamya S.; Zhang, Chaolin; Mentis, George Z.; Pellizzoni, Livio

doi:10.1038/s41593-021-00827-3

Cited by 125 publications

(109 citation statements)

References 49 publications

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“…AAV9-Lsm10/11 moderately improved motor function in SMA mice without affecting either weight or survival compared to GFP-injected SMA mice (Extended Data Fig. 5a-c), while AAV9-SMN robustly corrected all parameters as expected 21, 23–25 .…”

Section: U7 Snrnp Dysfunction Contributes To Neuromuscular Pathology In Sma Micementioning

confidence: 80%

“…2h-i). Such an increase was below the threshold of detection in CNS tissue, likely reflecting the much more widespread transduction of liver than CNS by AAV9 21 . Thus, Lsm10/11 co-expression selectively enhances U7 snRNP biogenesis in SMA mice in the absence of SMN modulation.…”

Section: Lsm10 and Lsm11 Co-expression Enhances U7 Snrnp Assemblymentioning

confidence: 96%

“…Sections were washed briefly in PBS and then blocked for 2 hours at room temperature in 10% normal donkey serum (Millipore) in 0.01M PBS containing 0.4% Triton X-100, pH 7.4. Immunostaining, washing, and mounting were then performed as previously described 21 . For NMJ analysis, freshly dissected QL and TA muscles were immersion-fixed in 4% PFA-PBS for 1 hour at room temperature, followed by a PBS wash and cryoprotection in 30% sucrose overnight at 4°C.…”

Section: Protein Analysismentioning

confidence: 99%

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SMN controls neuromuscular junction integrity through U7 snRNP

Tisdale

Alstyne

Simon

et al. 2021

Preprint

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The neuromuscular junction (NMJ) is an essential synapse for animal survival whose loss is a key hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). While insights into the function of the causative genes implicate RNA dysregulation in NMJ pathogenesis, the RNA-mediated mechanisms controlling the biology of this specialized synapse that go awry in disease remain elusive. Here, we show that activity of the SMA-determining SMN protein in the assembly of U7 small nuclear ribonucleoprotein (snRNP), which functions in the 3'-end processing of replication-dependent histone mRNAs, is required for NMJ integrity. AAV9-mediated gene delivery of U7-specific Lsm10 and Lsm11 proteins selectively enhances U7 snRNP assembly, corrects histone mRNA processing defects, and rescues key structural and functional abnormalities of neuromuscular pathology in SMA mice - including NMJ denervation, reduced synaptic transmission, and skeletal muscle atrophy. Furthermore, U7 snRNP dysfunction induced by SMN deficiency drives selective loss of the synaptic organizing protein Agrin at NMJs innervating vulnerable axial muscles of SMA mice, revealing an unanticipated link between U7-dependent histone mRNA processing and motor neuron-derived expression of an essential factor for NMJ biology. Together, these findings establish a direct contribution of U7 snRNP dysfunction to the neuromuscular phenotype in SMA and the requirement of RNA-mediated histone gene regulation for maintaining functional synaptic connections between motor neurons and muscles.

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Section: U7 Snrnp Dysfunction Contributes To Neuromuscular Pathology In Sma Micementioning

confidence: 80%

Section: Lsm10 and Lsm11 Co-expression Enhances U7 Snrnp Assemblymentioning

confidence: 96%

Section: Protein Analysismentioning

confidence: 99%

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SMN controls neuromuscular junction integrity through U7 snRNP

Tisdale

Alstyne

Simon

et al. 2021

Preprint

Self Cite

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“…However, the regulation and feedback that modulate SMN production by both mechanisms have not been elucidated yet. Recently, it has been reported that the overexpression of SMN protein by AAV9 has long-term neuronal toxic effects in a SMA mouse model [82]. Therefore, the putative overproduction of SMN with combinatorial therapies should also be cautiously considered in SMA patients, particularly in those who already received gene therapy.…”

Section: Evolving Therapies and The Importance Of Smn2mentioning

confidence: 99%

The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

Costa-Roger

Blasco-Pérez

Cuscò

et al. 2021

IJMS

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After 26 years of discovery of the determinant survival motor neuron 1 and the modifier survival motor neuron 2 genes (SMN1 and SMN2, respectively), three SMN-dependent specific therapies are already approved by FDA and EMA and, as a consequence, worldwide SMA patients are currently under clinical investigation and treatment. Bi-allelic pathogenic variants (mostly deletions) in SMN1 should be detected in SMA patients to confirm the disease. Determination of SMN2 copy number has been historically employed to correlate with the phenotype, predict disease evolution, stratify patients for clinical trials and to define those eligible for treatment. In view that discordant genotype-phenotype correlations are present in SMA, besides technical issues with detection of SMN2 copy number, we have hypothesized that copy number determination is only the tip of the iceberg and that more deepen studies of variants, sequencing and structures of the SMN2 genes are necessary for a better understanding of the disease as well as to investigate possible influences in treatment responses. Here, we highlight the importance of a comprehensive approach of SMN1 and SMN2 genetics with the perspective to apply for better prediction of SMA in positive neonatal screening cases and early diagnosis to start treatments.

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“…As compared to LVs, they possess high brain tissue tropism, desirable infection rate, and lower toxicity, immuno-stimulation, and decreased risk of causing disease in human. Yet, it is unclear how to set the precise level of expression of a transgene using AAVs [ 536 ]. In this respect, a transient activation in dividing cells might reveal to be the right approach.…”

Section: Precision Medicine For (Epi)genome Engineering and Their Possible Application To Treat Ndsmentioning

confidence: 99%

Chromatin Alterations in Neurological Disorders and Strategies of (Epi)Genome Rescue

et al. 2021

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Neurological disorders (NDs) comprise a heterogeneous group of conditions that affect the function of the nervous system. Often incurable, NDs have profound and detrimental consequences on the affected individuals’ lives. NDs have complex etiologies but commonly feature altered gene expression and dysfunctions of the essential chromatin-modifying factors. Hence, compounds that target DNA and histone modification pathways, the so-called epidrugs, constitute promising tools to treat NDs. Yet, targeting the entire epigenome might reveal insufficient to modify a chosen gene expression or even unnecessary and detrimental to the patients’ health. New technologies hold a promise to expand the clinical toolkit in the fight against NDs. (Epi)genome engineering using designer nucleases, including CRISPR-Cas9 and TALENs, can potentially help restore the correct gene expression patterns by targeting a defined gene or pathway, both genetically and epigenetically, with minimal off-target activity. Here, we review the implication of epigenetic machinery in NDs. We outline syndromes caused by mutations in chromatin-modifying enzymes and discuss the functional consequences of mutations in regulatory DNA in NDs. We review the approaches that allow modifying the (epi)genome, including tools based on TALENs and CRISPR-Cas9 technologies, and we highlight how these new strategies could potentially change clinical practices in the treatment of NDs.

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Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensorimotor circuit

Cited by 125 publications

References 49 publications

SMN controls neuromuscular junction integrity through U7 snRNP

SMN controls neuromuscular junction integrity through U7 snRNP

The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

Chromatin Alterations in Neurological Disorders and Strategies of (Epi)Genome Rescue

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