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).
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 reduced 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].
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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.