Could Some Emerging SMA Therapies Help Protect Motor Neurons in ALS?

Survival of the fittest motor neurons. Increasing SMN in reprogrammed neurons promoted their survival (Rodriguez-Muela et al, 2017). SMN may facilitate axon growth, stability and repair in motor neurons by helping to regulate the localized translation of key axonal proteins including GAP43 (Fallini et al., 2016).

A drop in levels of survival of motor neuron protein (SMN) may make motor neurons more vulnerable to ALS according to a study published on February 7 in Cell Reports. The study, led by Harvard Stem Cell Institute’s Lee Rubin in Massachusetts, found that the levels of SMN in ALS patient-derived neurons varied up to 4-fold and correlated with their longevity – at least in culture. In addition, increasing levels of SMN by blocking its degradation promoted the survival of these motor neurons. The findings come at the heels of a previous study led by University of Oxford’s Kevin Talbot in England which found that reduced levels of SMN increased the progression rate of a mouse model of SOD1 disease (Turner et al, 2009).

The results suggest that SMN may help protect motor neurons against ALS. Therefore, some emerging SMA therapies that boost SMN levels may help reduce motor neuron loss in people with the disease.

The study, which involved automated quantitative single cell immunofluorescence analysis of hundreds of SOD1, TDP-43 and c9orf72 reprogrammed neurons, aimed to tackle the heterogeneity inherent to the disease.

Researchers first suspected in the early 1990s that SMN may play a role in ALS because spinal muscular atrophy (SMA), which is due to SMN deficiency, also occurred in some families at risk of developing the disease (Appelbaum et al., 1992). But researchers subsequently ruled out the lack of SMN as a root cause of ALS due to the inability to detect mutations in the SMN1 gene in people with the disease (Orrell et al., 1997; Corcia et al., 2002; Blauw et al., 2012).

In more recent years, however, SMN copy number variants re-emerged as risk factors of ALS suggesting that reduced levels of these proteins may instead increase the susceptibility of developing the disease. People harboring only one copy of the SMN1 gene are at increased risk of developing ALS according to studies led by University of Tours’ Phillipe Corcia in France (Corcia et al., 2006). And, according to studies led by UMC Utrecht’s Leonard van den Berg in the Netherlands, reduced levels of SMN correlated with a greater risk of developing the disease (Veldink et al., 2005).

Duped by SMN? Both deletions and duplications of the SMN genes have been identified as potential risk factors of ALS (Corcia et al., 2002; Veldink et al., 2005; Blauw et al., 2012; Wang et al., 2014). But one study found no link in most of these cases (Blauw et al., 2012). And, one team found the deletion of SMN2 to be protective (Corcia et al., 2012). [Image: Farooq et al., 2015 under CC BY NC license.]

What’s more, lower levels of SMN may also exacerbate the disease. Reporting in 2005, the UMC Utrecht team found that reduced levels of SMN in people with sporadic ALS correlated with shorter survival time (Veldink et al. 2005).

Together, the findings suggest that lower levels of SMN may increase the vulnerability of motor neurons to ALS. Therefore, boosting SMN levels may help promote the survival of motor neurons in ALS and thereby, slow the progression of the disease.


Rodriguez-Muela N, Litterman NK, Norabuena EM, Mull JL, Galazo MJ, Sun C, Ng SY, Makhortova NR, White A, Lynes MM, Chung WK, Davidow LS, Macklis JD, Rubin LL. Single-Cell Analysis of SMN Reveals Its Broader Role in Neuromuscular Disease. Cell Rep. 2017 Feb 7;18(6):1484-1498. [PubMed].

Fallini C, Donlin-Asp PG, Rouanet JP, Bassell GJ, Rossoll W. Deficiency of the Survival of Motor Neuron Protein Impairs mRNA Localization and Local Translation in the Growth Cone of Motor Neurons. J Neurosci. 2016 Mar 30;36(13):3811-20. [PubMed].

Turner BJ, Parkinson NJ, Davies KE, Talbot K. Survival motor neuron deficiency enhances progression in an amyotrophic lateral sclerosis mouse model. Neurobiol Dis. 2009 Jun;34(3):511-7. [PubMed].

Appelbaum JS, Roos RP, Salazar-Grueso EF, Buchman A, Iannaccone S, Glantz R, Siddique T, Maselli R. Intrafamilial heterogeneity in hereditary motor neuron disease. Neurology. 1992 Aug;42(8):1488-92. [PubMed].

Orrell RW, Habgood JJ, de Belleroche JS, Lane RJ. The relationship of spinal muscular atrophy to motor neuron disease: investigation of SMN and NAIP gene deletions in sporadic and familial ALS. J Neurol Sci. 1997 Jan;145(1):55-61. [PubMed].

Corcia P, Khoris J, Couratier P, Mayeux-Portas V, Bieth E, De Toffol B, Autret A, Müh JP, Andres C, Camu W. SMN1 gene study in three families in which ALS and spinal muscular atrophy co-exist. Neurology. 2002 Nov 12;59(9):1464-6. [PubMed].

Blauw HM, Barnes CP, van Vught PW, van Rheenen W, Verheul M, Cuppen E, Veldink JH, van den Berg LH. SMN1 gene duplications are associated with sporadic ALS. Neurology. 2012 Mar 13;78(11):776-80. [PubMed].

Corcia P, Camu W, Halimi JM, Vourc’h P, Antar C, Vedrine S, Giraudeau B, de Toffol B, Andres CR; French ALS Study Group. SMN1 gene, but not SMN2, is a risk factor for sporadic ALS. Neurology. 2006 Oct 10;67(7):1147-50. [PubMed].

Veldink JH, Kalmijn S, Van der Hout AH, Lemmink HH, Groeneveld GJ, Lummen C, Scheffer H, Wokke JH, Van den Berg LH. SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS. Neurology. 2005 Sep 27;65(6):820-5. [PubMed].

Turner BJ, Alfazema N, Sheean RK, Sleigh JN, Davies KE, Horne MK, Talbot K. Overexpression of survival motor neuron improves neuromuscular function and motor neuron survival in mutant SOD1 mice. Neurobiol Aging. 2014 Apr;35(4):906-15. [PubMed].

On the home page: The structure of the tudor domain of SMN. Image: Selenko et al., 2001. PDB.

disease-als disease-sma SMN topic-preclinical
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