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:10.1101/2022.03.13.484188

Cited by 11 publications

(18 citation statements)

References 66 publications

(87 reference statements)

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“…Denervation and sprouting can occur simultaneously in different parts of the same motor unit [26], and in one human early stage case NMJ denervation also preceded motor neuron loss [2]. Recent studies show similar findings in STMN2 null mice, a protein that regulates microtubule stability and neurite outgrowth [27,28], whose depletion occurs downstream of TDP-43 ablation [29]. The use of intravital confocal microendoscopy could help gain further data directly in humans and have biomarker potential too [30].…”

Section: Are Distal Axon Structures Lost Before More Proximal Regions?mentioning

confidence: 85%

“…Moreover, SOD1 transgenic mouse models of ALS show little or no improvement when programmed axon death is blocked, either at the NMNAT (WLD S ) level or the SARM1 level [88,89] despite some evidence that the soma is impaired very early in these models [41]. NMJ denervation following STMN2 depletion is also independent of SARM1 [29], and glial-derived toxicity, or loss of glial support are further mechanisms that may contribute [90].…”

Section: One Mechanism Several or Many?mentioning

confidence: 99%

“…TDP-43 has a role in regulating local translation in axons [45] that influences the axonal transcriptome [105] and appears to have pathogenic potential [106]. The early denervation of NMJs in mice lacking TDP-43 target STMN2 [29] could represent one mechanism by which TDP-43 influences the survival of axonal compartments directly.…”

Section: Axon-intrinsic Eventsmentioning

confidence: 99%

“…The emerging links to SARM1, including the GWAS association of its chromosomal locus [73], suggest there could be a common SARM1dependent mechanism. STMN2 depletion also appears to be a common mechanism influencing NMJ innervation, although perhaps not in a SARM1-dependent manner [29]. Thus, addressing these two, potentially independent contributors to axon and NMJ survival, are promising directions for axonal therapies, and they could be especially effective in combination with methods to increase compensatory sprouting.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

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Axon Biology in ALS: Mechanisms of Axon Degeneration and Prospects for Therapy

Coleman

2022

Neurotherapeutics

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This review addresses the longstanding debate over whether amyotrophic lateral sclerosis (ALS) is a ‘dying back’ or ‘dying forward’ disorder in the light of new gene identifications and the increased understanding of mechanisms of action for previously identified ALS genes. While the topological pattern of pathology in animal models, and more anecdotally in patients is indeed ‘dying back’, this review discusses how this fits with the fact that many of the major initiating events are thought to occur within the soma. It also discusses how widely varying ALS risk factors, including some impacting axons directly, may combine to drive a common pathway involving TAR DNA binding protein 43 (TDP-43) and neuromuscular junction (NMJ) denervation. The emerging association between sterile alpha and TIR motif-containing 1 (SARM1), a protein so far mostly associated with axon degeneration, and sporadic ALS is another major theme. The strengths and limitations of the current evidence supporting an association are considered, along with ways in which SARM1 could become activated in ALS. The final section addresses SARM1-based therapies along with the prospects for targeting other axonal steps in ALS pathogenesis.

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Section: Are Distal Axon Structures Lost Before More Proximal Regions?mentioning

confidence: 85%

Section: One Mechanism Several or Many?mentioning

confidence: 99%

Section: Axon-intrinsic Eventsmentioning

confidence: 99%

Section: Summary and Perspectivesmentioning

confidence: 99%

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Axon Biology in ALS: Mechanisms of Axon Degeneration and Prospects for Therapy

Coleman

2022

Neurotherapeutics

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“…The gene showing the strongest reduction in expression by TDP-43 proteinopathy is STMN2 [28 ▪▪ ]. In mice, Stmn2 deficiency disrupts microtubule dynamics in motor neurons and precipitates a motor neuropathy [29 ▪ ,30 ▪ ], stressing its significance in ALS pathophysiology. UNC13A , encoding a critical synaptic protein, is another prominent gene whose expression is reduced by TDP-43 proteinopathy [27 ▪▪ ].…”

Section: Novel Mechanisms Of Known Amyotrophic Lateral Sclerosis Genesmentioning

confidence: 99%

Update on genetics of amyotrophic lateral sclerosis

Brenner

Freischmidt

2022

Current Opinion in Neurology

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Purpose of reviewALS genetics are highly dynamic and of great interest for the ALS research community. Each year, by using ever-growing datasets and cutting-edge methodology, an array of novel ALS-associated genes and downstream pathomechanisms are discovered. The increasing plenty and complexity of insights warrants regular summary by-reviews.Recent findingsMost recent disease gene discoveries constitute the candidate and risk genes SPTLC1, KANK1, CAV1, HTT, and WDR7, as well as seven novel risk loci. Cell type and functional enrichment analyses enlighten the genetic basis of selective motor neuron vulnerability in ALS demonstrating high expression of ALS-associated genes in cortical motor neurons and highlight the pathogenic significance of cell-autonomous processes. Major pathomechanistic insights have been gained regarding known ALS genes/proteins, specifically C9orf72, TDP43, ANXA11, and KIF5A. The first ASO-based gene-specific therapy trials in familial forms of ALS have yielded equivocal results stressing the re-evaluation of pathomechanisms linked to SOD1 and C9orf72 mutations.SummaryThe genetic and molecular basis of ALS is increasingly examined on single-cell resolution. In the past 2 years, the understanding of the downstream mechanisms of several ALS genes and TDP-43 proteinopathy has been considerably extended. These insights will result in novel gene specific therapy approaches for sporadic ALS and genetic subtypes.

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Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation

López-Erauskin¹,

Bravo‐Hernández

Presa

et al. 2022

Preprint

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The human mRNA most affected by TDP-43 loss-of-function is transcribed from the STMN2 gene and encodes stathmin-2 (also known as SCG10), whose loss is a neurodegenerative disease hallmark. Here using multiple in vivo approaches, including transient antisense oligonucleotide (ASO)-mediated suppression, chronic shRNA-mediated depletion in aging mice, and germline deletion, we establish stathmin-2 to be essential for acquisition and maintenance of neurofilament-dependent structuring of axoplasm critical for maintaining diameter and conduction velocity of large-myelinated axons. Sustained stathmin-2 loss from an otherwise mature adult nervous system is demonstrated over a time course of eight months to initiate and drive motor neuron disease that includes 1) shrinkage in inter-neurofilament spacing that is required to produce a three-dimensional space filling array that defines axonal caliber, 2) collapse of mature axonal caliber with tearing of outer myelin layers, 3) reduced conduction velocity, 4) progressive motor and sensory deficits (including reduction of the pain transducing neuropeptide CGRP), and 5) muscle denervation. Demonstration that chronic stathmin-2 reduction is itself sufficient to trigger motor neuron disease reinforces restoration of stathmin-2 as an attractive therapeutic approach for TDP-43-dependent neurodegeneration, including the fatal adult motor neuron disease ALS.

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

Cited by 11 publications

References 66 publications

Axon Biology in ALS: Mechanisms of Axon Degeneration and Prospects for Therapy

Axon Biology in ALS: Mechanisms of Axon Degeneration and Prospects for Therapy

Update on genetics of amyotrophic lateral sclerosis

Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation

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