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...  Read more

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.

References:
Higashi S, Tsuchiya Y, Araki T, Wada K, Kabuta T (2010) TDP-43 Physically Interacts with Amyotrophic Lateral Sclerosis-Linked Mutant CuZn Superoxide Dismutase. Neurochem Int. 2010 Oct. 7. Abstract

Koistinen H, Prinjha R, Soden P, Harper A, Banner SJ, Pradat PF, Loeffler JP, Dingwall C (2006) Elevated levels of amyloid precursor protein in muscle of patients with amyotrophic lateral sclerosis and a mouse model of the disease. Muscle Nerve 34:444-50. Abstract

Küst BM, Brouwer N, Mantingh IJ, Boddeke HW, Copray JC (2003) Reduced p75NTR expression delays disease onset only in female mice of a transgenic model of familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 4(2):100-5. Abstract

Lowry KS, Murray SS, McLean CA, Talman P, Mathers S, Lopes EC, Cheema SS (2001) A potential role for the p75 low-affinity neurotrophin receptor in spinal motor neuron degeneration in murine and human amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2(3):127-34. Abstract

Pehar M, Cassina P, Vargas MR, Castellanos R, Viera L, Beckman JS, Estevez AG, Barbeito L (2004) Astrocytic production of nerve growth factor in motor neuron apoptosis: implications for amyotrophic lateral sclerosis. J Neurochem 89:464-73. Abstract

Troy CM, Friedman JE, Friedman WJ (2002) Mechanisms of p75-mediated death of hippocampal neurons. Role of caspases. J Biol Chem 277(37):34295-302. Abstract

Turner BJ, Cheah IK, Macfarlane KJ, Lopes EC, Petratos S, Langford SJ, Cheema SS (2003) Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice. J Neurochem 87(3):752-63. Abstract

Turner BJ, Murray SS, Piccenna LG, Lopes EC, Kilpatrick TJ, Cheema SS (2004) Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice. J Neurosci Res 78(2):193-9. Abstract

Turner BJ, Ackerley S, Davies KE, Talbot K (2010) Dismutase-competent SOD1 mutant accumulation in myelinating Schwann cells is not detrimental to normal or transgenic ALS model mice. Hum Mol Genet 19(5):815-24. Abstract

Yoon EJ, Park HJ, Kim GY, Cho HM, Choi JH, Park HY, Jang JY, Rhim HS, Kang SM (2009) Intracellular amyloid beta interacts with SOD1 and impairs the enzymatic activity of SOD1: implications for the pathogenesis of amyotrophic lateral sclerosis. Exp Mol Med 41(9):611-7. Abstract

View all comments by Rudolf Bloechl

Trophos made sure that olesoxime had all the basic criteria for a clinical trial; indeed, this molecule had yielded very convincing results on motor neuron survival in several pathological setups in animal models. Unfortunately, olesoxime did not extend survival of ALS patients. As with other unsuccessful trials, this failure underlines the difficulty of treating a progressive disease with symptoms appearing in late adulthood. I have several comments on this point.

First, this result does not jeopardize the clinical trial ongoing on spinal muscular atrophy (SMA) patients: That SMA patients can be identified genetically, and that the disease is progressing much earlier and more slowly, allow for a more timely treatment.

Second, olesoxime, although ineffective in treating symptomatic patients, could still prove to be part of a combination of molecules in the future.

Nevertheless, these negative results, added to the numerous unsuccessful past trials, raise the question of the suitability of our experimental models, which are mostly murine (and this is true for almost...  Read more

Trophos made sure that olesoxime had all the basic criteria for a clinical trial; indeed, this molecule had yielded very convincing results on motor neuron survival in several pathological setups in animal models. Unfortunately, olesoxime did not extend survival of ALS patients. As with other unsuccessful trials, this failure underlines the difficulty of treating a progressive disease with symptoms appearing in late adulthood. I have several comments on this point.

First, this result does not jeopardize the clinical trial ongoing on spinal muscular atrophy (SMA) patients: That SMA patients can be identified genetically, and that the disease is progressing much earlier and more slowly, allow for a more timely treatment.

Second, olesoxime, although ineffective in treating symptomatic patients, could still prove to be part of a combination of molecules in the future.

Nevertheless, these negative results, added to the numerous unsuccessful past trials, raise the question of the suitability of our experimental models, which are mostly murine (and this is true for almost all trials).

Perhaps we should look into new tools such as induced pluripotent stem cells taken from ALS patients and derived into motor neurons. They could generate more pertinent models. These results also emphasize the continuous necessity for basic research support, in particular, to fund programs aimed at understanding the origin and first triggers of the disease. Indeed, finding ways of blocking such early triggers, combined with serious epidemiological studies to determine whether some populations are more at risk for disease because of environmental or other reasons, could ultimately lead to the development of preventive treatments. Although this negative result has certainly been disappointing to both patients and Trophos, the key for success is in basic and clinical researchers continuing to work together with companies such as Trophos. One day it will work!

View all comments by Brigitte Pettmann

I would wonder whether addressing mitochondrial function, one of the earliest events in ALS (presymptomatic), would be overwhelmed by other factors driving disease once symptomatic and, hence, diagnosable with current methods. I am in the camp of neuroinflammation driving progression, and still think olesoxime and/or dexpramipexole (which I also suspect might suffer the same issue as olesoxime did) can be valuable ingredients of a cocktail-style treatment plan that addresses the inflammatory component as well.

View all comments by Eric Valor