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

Krus, Kelsey L; Strickland, Amy; Yamada, Yurie; DeVault, Laura; Schmidt, Robert E.; Bloom, A. Joseph; Milbrandt, Jeffrey; DiAntonio, Aaron

doi:10.1016/j.celrep.2022.111001

Cited by 49 publications

(52 citation statements)

References 73 publications

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“…Post-mortem analysis of ALS patient spinal cord tissue showed an overall reduction in functional STMN2 transcript expression when compared to controls, with higher expression of the truncated STMN2 -mRNA transcripts [ 198 , 199 ]. In a recent in vivo study, STMN2 -knockout mice were shown to recapitulate aspects of ALS neuromuscular pathology, providing further support for a critical role for STMN2 expression in ALS pathology [ 200 ]. STMN2 -knockout mice demonstrated significant distal muscular weakness and loss of neuromuscular junctions in the periphery, as well as demonstrating sensory deficits concurrent with the ALS phenotype.…”

Section: Current Treatmentmentioning

confidence: 99%

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

Roberts

Theunissen

Mastaglia

et al. 2022

IJMS

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Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress with patient care. Alpha-synuclein (αSyn) is a hallmark for disease in neurodegenerative disorders, such as Parkinson’s disease, Lewy body dementia, and multiple system atrophy. A growing body of evidence now suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. This review endeavours to capture the scope of literature regarding the aetiology and development of ALS and its commonalities with “synucleinopathy disorders”. We will discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.

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Section: Current Treatmentmentioning

confidence: 99%

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

Roberts

Theunissen

Mastaglia

et al. 2022

IJMS

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“…Stathmin-2 is a neuronally enriched protein that plays a crucial role in axonal outgrowth during development ( 27 ) and regeneration ( 25 , 26 , 28 ). Developmental deletion of mouse Stmn2 causes motor deficits with denervation of neuromuscular junctions ( 29 , 30 ). Among the four members of the stathmin gene family, stathmin-2 has the highest expression in mouse and human motor neurons ( 25 ); STMN2 is among the top 20 most enriched mRNAs in the ALS-vulnerable motor neurons of the anterior gray column of the spinal cord ( 25 , 31 ).…”

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confidence: 99%

Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies

Baughn

Melamed

López-Erauskin

et al. 2023

Science

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Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre–messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3′ splice site in STMN2 pre-mRNA. Targeting dCasRx or antisense oligonucleotides (ASOs) suppressed cryptic splicing, which restored axonal regeneration and stathmin-2–dependent lysosome trafficking in TDP-43–deficient human motor neurons. In mice that were gene-edited to contain human STMN2 cryptic splice-polyadenylation sequences, ASO injection into cerebral spinal fluid successfully corrected Stmn2 pre-mRNA misprocessing and restored stathmin-2 expression levels independently of TDP-43 binding.

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“…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.

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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.

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

Cited by 49 publications

References 73 publications

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies

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

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