. Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis. J Clin Invest. 2010 Oct 1;120(10):3673-9. PubMed.

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  1. Reyes et al. report that the mitochondrial apoptotic pathway crucially contributes to degeneration and death of motor neurons in ALS of SOD1-G93A mice. This pathway is also induced by the neurotrophin receptor p75 (see, e.g., Troy et al., 2002), and earlier reports have linked p75 to ALS (e.g., Lowry et al., 2001). In particular, NGF from reactive astrocytes can cause motor neuronal apoptosis via p75 (Pehar et al., 2004).

    However, neither p75 knockout (deletion of p75 exon 3) in SOD1-G93A mice (Küst et al., 2003) nor application of a cyclic decapeptide against the N-terminal region of p75 (Turner et al., 2004) significantly influence onset and progression of ALS; on the other hand, application of antisense peptide nucleotides against p75 delays and attenuates ALS (Turner et al., 2003). These seemingly contradictory results can be reconciled by considering the (normally weak) expression of the truncated form of p75, s-p75, that can also be found in p75 exon 3 knockout mice and that (like p75) reaches significant levels in sciatic nerves of SOD1-G93A mice by endstage ALS (Turner et al., 2009). The s-p75 lacks the N-terminal cysteine-rich domains of p75, and hence the neurotrophin- and Aβ-binding sites within this region, but still encompasses a second Aβ-binding site in the extracellular juxtamembrane region of p75; evidence of this binding site is presented in my Aβ-crosslinker-hypothesis).

    The hypothesis suggests that oligomeric Aβ can crosslink p75, via this extracellular juxtamembrane binding site, with other surface proteins such as APP, α-synuclein, and prion protein, and that this crosslinking represents an important physiological function of Aβ. Under pathophysiological conditions, however, β-sheet aggregates of certain amyloidogenic proteins can cause p75-mediated cell degeneration and apoptosis when they form complexes with Aβ species and use Aβ to interact with the juxtamembrane binding site of p75. Amyloid aggregates that can activate p75 and s-p75 through this binding site include, for example, β-sheet Aβ and NAC, a natural fragment of α-synuclein, and may also include secreted SOD1 aggregates since SOD1 and especially SOD1-G93A can directly interact with Aβ (Yoon et al., 2009); TDP-43, too, has been reported to interact with Aβ (Higashi et al., 2010), but it is unknown if TDP-43 is secreted as well. In addition, Aβ aggregates may contribute to peripheral motor neuron degeneration and to motor neuronal death by irregular activation of p75 and s-p75 as APP and Aβ are increased in certain muscle groups of ALS patients and of SOD1-G93A mice (Koistinen et al., 2006). Although not the basic cause of ALS, p75 and s-p75 signaling may crucially aggravate the disease in the described ways.

    Reyes et al. conclude that targeting processes that induce the mitochondrial apoptotic pathway might be a useful therapeutic strategy for ALS and related motor neuron diseases. The neurotrophin receptor p75 and its truncated form s-p75 certainly are worthwhile objects of such research.

    View all comments by Rudolf Bloechl