SMA proteins

The discovery of axonal SMN (a-SMN) - presented here through an interview to researchers Giorgio Battaglia and Enrico Garattini - is certainly interesting and very important, but to understand fully its meaning it needs a set of preliminary remarks about basic concepts concerning the spinal muscular atrophy (SMA).

The SMA linked to chromosome 5 (more than 98%) arise from the so-called deletion (absence) homozygous of SMN1 gene (telomeric copy, or located to the extremity of chromosome), which follows the deficiency of the protein SMN complete (full-length, now we'll call it SMNfl). The other copy of the SMN gene - called SMN2 or centromeric (located at the center of the chromosome) - produces a small proportion of protein SMNfl and a predominant share of SMN protein reduced in length. The disease is caused by the deletion of the telomeric gene and since the two genes are identical in everything except for five nucleotides and produce different amounts of protein SMNfl, it was deduced and demonstrated that only the latter is able to cause SMA.
We know also that the protein SMNfl is ubiquitous; it is present not only in the motor neurons, but also in almost all other body tissues. From this comes one of the main problems relating to SMA: why are the clinical symptoms related to the loss of the motor neurons, if they stem from the lack of a ubiquitous protein? And consequently, does SMNfl play for motorn neurons a different function? Are the motor neurons, for their unique role, particularly susceptible to loss of protein SMNfl?

Several authoritative studies have shown that the protein SMNfl plays a key role in the so-called ribosomal metabolism, thus contributing substantially to the cell survival. For a long time, however, studies in vitro (cell culture) and also in animal models have raised doubts that in the events of SMA pathogenetic can also play a role the interaction between the end of the nerve fibre and muscle.
In addition, from 2000 onwards, several studies have shown - in animal models - that the SMN protein plays a fundamental role in axonal growth of motor neurons (the axon, remember, is the extension of greater length of nerve cell). In particular, it has been found in the so-called growth cones (structures highly specialized site in the terminal of the axon, appointed to manage the growth of the latter to the correct destination), both in cell cultures and in vivo; here it is not together to protein Gemin2, which play an extremely important function in motor neurons, right along with SMN. The fact that SMN and Gemini 2 are not set in axons suggests that SMN performs a different and specific function.
It should be pointed out again that in axons the SMN protein has other "partners" with which it carries out its functions, one of which is called hnRNP (highly related RNA-binding heterogeneous nuclear ribonucleoproteins R) and is part of a group of about thirty proteins deputate to "bind" the pre-mRNA (messenger RNA) and m-RNA, playing critical roles in all stages.
A recent study by Wilfried Rossoll, Sibylle Jablonka, Catia Andreassi, Ann-Kathrin Kröning, Kathrin Karle, Umrao R. the Universities of Würzburg (Germany) and Ohio (USA) has shown, finally, the role of SMN protein and its "partner" hnRNP in axonal growth of the motor neurons.

Returning to the study of Giorgio Battaglia and Enrico Garattini, it has allowed the identification of an additional transcript of SMN1 gene, called a-SMN, which is an axonal protein specifically expressed selectively in motor neurons, mainly localized in axons, with a specific function on the growth of the motor neurons.
A first step should be noted with reference to the same article, where it reports the need to verify the real meaning of a-SMN for the genesis of SMA: it should be added that in the animal model (mouse) was shown that before the death of the cell body of motor neuron, there is a massive axonal loss and in 2006 a work by Jablonka and others (London-Berlin) has shown that, in particularly severe murine forms, even some sensory neurons are involved and show a reduced axonal growth (in human disease, there are no changes in sensitivity).
Other elements to be included are also the great "nuclear" role played by SMNfl protein and the big work remaining to be done to understand what is the relative contribution of protein SMNfl and a-SMN in neuronal degeneration and thus in the pathogenesis of SMA.

All the discoveries and the studies referred above are of great scientific importance and of great value in advancing the understanding of basic mechanisms of SMA, but these are studies carried out in the laboratory, in animal models and/or cell culture.
It is therefore necessary to underline the differences between these models and clinical reality, and - without ever "off" the hope – to understand the enormous importance of a study that progresses through stages scientifically rigorous, so that therapeutic efforts are not hasty and unnecessary (or harmful) and conducted only under the pressure to discovery a cure.

(source: UILDM website)