Loss of mouse Stmn2 function causes motor neuropathy

Juan, Irune Guerra San; Nash, Leslie A.; Smith, Kevin S.; Leyton-Jaimes, Marcel F.; Qian, Menglu; Klim, Joseph R.; Limone, Francesco; Dorr, Alexander B.; Couto, Alexander Benavides; Pintacuda, Greta; Joseph, Brian; Whisenant, D. Eric; Noble, Caroline; Melnik, Veronika; Potter, Deirdre; Holmes, Amie L.; Verhage, Matthijs; Eggan, Kevin

doi:10.1016/j.neuron.2022.02.011

Cited by 44 publications

(41 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While this article was under review, Guerra San Juan et al ( Guerra San Juan et al, 2022 ) described a genetically distinct Stmn2 KO mouse and their findings are in excellent agreement with ours. Both studies showed that the loss of STMN2 impairs microtubule dynamics, and that constitutive STMN2 loss causes early motor deficits with denervation of skeletal muscle and endplate fragmentation and without spinal cord motor neuron loss.…”

Section: Discussionsupporting

confidence: 87%

Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy

et al. 2022

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 87%

Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy

et al. 2022

View full text Add to dashboard Cite

“…One mechanism of disease recently implicated in ALS and FTLD-TDP links the loss of nuclear TDP-43 to mis-splicing and depletion of stathmin 2 ( STMN2 ), a regulator of the microtubule cytoskeleton ( Klim et al, 2019 ; Melamed et al, 2019 ; Prudencio et al, 2020 ; Pickles et al, 2022 ). Given the importance of microtubules for normal neuron function, it is noteworthy that two independent studies have now demonstrated that stathmin deficiency leads to motor dysfunction in mouse models ( Guerra San Juan et al, 2022 ; Krus et al, 2022 ).…”

Section: Transactivation Response Element Dna-binding Protein 43 Clea...mentioning

confidence: 99%

TDP-43 and NEAT long non-coding RNA: Roles in neurodegenerative disease

Sekar

Tusubira²,

Ross³

2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Understanding and ameliorating neurodegenerative diseases represents a key challenge for supporting the health span of the aging population. Diverse protein aggregates have been implicated in such neurodegenerative disorders, including amyloid-β, α-synuclein, tau, fused in sarcoma (FUS), and transactivation response element (TAR) DNA-binding protein 43 (TDP-43). Recent years have seen significant growth in our mechanistic knowledge of relationships between these proteins and some of the membrane-less nuclear structures that fulfill key roles in the cell function. These include the nucleolus, nuclear speckles, and paraspeckles. The ability of macromolecular protein:RNA complexes to partition these nuclear condensates through biophysical processes that involve liquid–liquid phase separation (LLPS) has also gained attention recently. The paraspeckle, which is scaffolded by the architectural long-non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) plays central roles in RNA processing and metabolism and has been linked dynamically to TDP-43. In this mini-review, we outline essential early and recent insights in relation to TDP-43 proteinopathies. We then appraise the relationships between TDP-43 and NEAT1 in the context of neuronal paraspeckles and neuronal stress. We highlight key areas for investigation based on recent advances in our understanding of how TDP-43 affects neuronal function, especially in relation to messenger ribosomal nucleic acid (mRNA) splicing. Finally, we offer perspectives that should be considered for translational pipelines in order to improve health outcomes for the management of neurodegenerative diseases.

show abstract

“…Moreover, it was recently shown that the introduction of the human STMN2 gene is able to rescue the motor phenotype in mice deficient for Stmn2 ( Stmn2‐/‐ ). 31 …”

Section: Cryptic Splicing Events As Therapeutic Targetsmentioning

confidence: 99%

“…Moreover, it was recently shown that the introduction of the human STMN2 gene is able to rescue the motor phenotype in mice deficient for Stmn2 (Stmn2-/-). 31 Another approach could be to reduce or prevent cryptic splicing events from happening, even in the face of TDP-43 dysfunction. Antisense oligonucleotides (ASOs) are chemically modified oligonucleotides that alter RNA targets, including triggering their degradation or modulating pre-mRNA splicing.…”

Section: Cryptic Splicing Events As Therapeutic Targetsmentioning

confidence: 99%

“…Upregulating STMN2 levels with a lentivirus delivering the stathmin‐2 gene 7 or by stabilising it via small molecule inhibition of c‐Jun N‐terminal kinase 8 rescues impaired axonal regeneration and cell death caused by TDP‐43 loss in human‐induced pluripotent stem cell‐derived motor neurons. Moreover, it was recently shown that the introduction of the human STMN2 gene is able to rescue the motor phenotype in mice deficient for Stmn2 ( Stmn2‐/‐ ) 31 …”

Section: Cryptic Splicing Events As Therapeutic Targetsmentioning

confidence: 99%

See 1 more Smart Citation

Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

Akiyama

Koike

Petrucelli

et al. 2022

Clinical & Translational Med

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating human neurodegenerative diseases. A hallmark pathological feature of both diseases is the depletion of the RNA‐binding protein TDP‐43 from the nucleus in the brain and spinal cord of patients. A major function of TDP‐43 is to repress the inclusion of cryptic exons during RNA splicing. When it becomes depleted from the nucleus in disease, this function is lost, and recently, several key cryptic splicing targets of TDP‐43 have emerged, including STMN2 , UNC13A , and others. UNC13A is a major ALS/FTD risk gene, and the genetic variations that increase the risk for disease seem to do so by making the gene more susceptible to cryptic exon inclusion when TDP‐43 function is impaired. Here, we discuss the prospects and challenges of harnessing these cryptic splicing events as novel therapeutic targets and biomarkers. Deciphering this new cryptic code may be a touchstone for ALS and FTD diagnosis and treatment.

show abstract

Loss of mouse Stmn2 function causes motor neuropathy

Cited by 44 publications

References 80 publications

Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy

Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy

TDP-43 and NEAT long non-coding RNA: Roles in neurodegenerative disease

Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

Contact Info

Product

Resources

About