Klim JR, Williams LA, Limone F, Guerra San Juan I, Davis-Dusenbery BN, Mordes DA, Burberry A, Steinbaugh MJ, Gamage KK, Kirchner R, Moccia R, Cassel SH, Chen K, Wainger BJ, Woolf CJ, Eggan K. ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nat Neurosci. 2019 Feb;22(2):167-179. Epub 2019 Jan 14 PubMed.

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Comments

  1. I really like these papers. We always say that TDP-43 mislocalization is the "pathological hallmark of ALS," but the real pathological event that profoundly affects patients happens at the neuromuscular junction. Indeed, the dying back of the motor axons from the muscle is what actually leads to paralysis, and so the connections that these papers make between the loss of functional TDP-43, stathmin-2, and axonal integrity and regeneration mark an important advance to really getting at what this disease is all about from a clinical perspective. Of course, big questions remain about what the upstream initiator of TDP-43 dysfunction is in the vast majority of sporadic ALS cases, but at least now these papers convincingly point to one critical downstream consequence.

    View all comments by Krista Spiller

  2. It is encouraging that two different groups have come to very similar conclusions regarding stathmin 2. Therapeutically, one wonders whether antisense to modulate splicing of stathmin 2 might be useful. However, the stathmin 2 hypothesis is dependent on loss of TDP-43 function being the predominant pathogenic process in ALS, yet there is growing evidence that TDP-43 levels are increased in ALS, and that ALS linked TDP-43 mutations actually cause a gain of function rather than loss. More work needs to be done.

    View all comments by Jemeen Sreedharan

  3. While previous studies support the notion that repression of TDP-43 cryptic exons is compromised in neurodegenerative disease exhibiting TDP-43 pathology (Ling et al., 2015; Sun et al., 2017), including ALS, identification of direct targets of such a splicing defect that would impact on physiology of motor neurons has been elusive.

    Using human fibroblast- or iPSC-derived motor neurons, this pair of papers now provides compelling evidence to support stathmin-2 (STMN2), a protein regulating neuronal growth and enriched in motor neurons, as one such target. Upon depletion of TDP-43, Melamed and colleagues found incorporation into its pre-RNA a non-conserved cryptic exon containing a UG-rich TDP-43 binding element within intron 1 of STMN2. This non-conserved cryptic exon contained a poly(A) site, selection of which would lead to a truncated nonfunctional transcript; consequently, it is predicted that the level of mature STMN2 mRNA would be markedly diminished. They not only confirmed this prediction in neurons derived from trans-differentiation of ALS fibroblasts carrying mutant TDP-43, but also from motor cortex and spinal motor neurons from familial (C9ORF72) and sporadic ALS. A second prediction from such incorporation of STMN2 cryptic exon when TDP-43 was depleted would be a corresponding reduction in level of STMN2 protein. Using spinal cord tissues from ALS cases, Klim and colleagues showed that this prediction was nicely borne out. Finally, using an in vitro axotomy paradigm, these investigators validated the functional impact of losing STMN2 as a result of depleting TDP-43 in motor neurons. These data thus showed convincingly the critical role of TDP-43 in repressing non-conserved cryptic exons, particularly that of STMN2, in motor neurons of ALS.

    Despite these advances, an outstanding question is whether reduction in STMN2 upon deficits in TDP-43 splicing repression represents the major contributor to neurodegeneration in motor neurons of ALS patients. As opposed to STMN’s role in regenerative capacity of immature motor neurons, could other TDP-43 cryptic exon targets, such as those documented in both papers, contribute to neurodegeneration of mature, myelinated motor neurons in adults? While STMN2 can be an attractive target for development of ALS therapy, unraveling this issue in the future will provide critical information regarding its therapeutic potential as well as alternative strategies, including those that directly target TDP-43 splicing repression.

    References:

    Ling JP, Pletnikova O, Troncoso JC, Wong PC. NEURODEGENERATION. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science. 2015 Aug 7;349(6248):650-5. PubMed.

    Sun M, Bell W, LaClair KD, Ling JP, Han H, Kageyama Y, Pletnikova O, Troncoso JC, Wong PC, Chen LL. Cryptic exon incorporation occurs in Alzheimer's brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43. Acta Neuropathol. 2017 Jun;133(6):923-931. Epub 2017 Mar 22 PubMed.

    View all comments by Philip Wong

  4. These are a pair of exciting papers that implicate loss of stathmin-2 as downstream of loss of TDP-43 that could be disruptive to neuronal health and contribute to neurodegeneration in ALS and FTD. The big question that remains, which is outside the scope of these studies, is whether loss of TDP-43 is a primary driver in ALS/FTD as opposed to toxic gain of function mechanisms, and if so how much stathmin-2 is responsible for neuronal damage versus the many other genes disrupted by loss of TDP-43 previously reported by this group and others. Regardless, these papers represent a very exciting and important step forward.

    View all comments by Robert Baloh

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