Palma E, Inghilleri M, Conti L, Deflorio C, Frasca V, Manteca A, Pichiorri F, Roseti C, Torchia G, Limatola C, Grassi F, Miledi R. Physiological characterization of human muscle acetylcholine receptors from ALS patients. Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20184-8. PubMed.
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Université de Strasbourg
This is a highly interesting paper. In my opinion, this paper shows that muscles of ALS patients are not "simply" denervated muscles. Their acetylcholine receptors are different in electrophysiological properties from patients with non-ALS denervation. This suggests intrinsic pathological mechanisms in muscles of ALS patients. This fits with recent studies in the field that show that muscle defects are able, on their own, to trigger neuromuscular changes related to ALS. A major lack of this study is some mechanistic insights: As the authors point out, they do not provide molecular information to explain this difference between ALS and denervated muscles. Future studies should determine whether the transcription of neuromuscular junction genes is somewhat impaired in ALS muscles, or if the defect lies post-transcriptionally. Despite the exciting result, a drawback of this study is that it lacks a healthy control group to compare with ALS patients.
In all, this is another piece of evidence strengthening the idea that ALS is not a disease restricted to motor neurons, but also involves other cell types, including the skeletal muscle.
Sapienza University of Rome
In this study, the authors develop an experimental method to further study the muscle pathophysiology of ALS and to better test the so-called “dying-back model.”
In fact, although most efforts have aimed to define the potential genes and pathways associated with motor neuron degeneration and to understand ALS pathogenesis, no consensus has emerged as to the primary toxicity of gene mutations. The primary causes of ALS are therefore still unknown and no effective or decisive treatments are available.
Although the steps that lead to the pathological state are well defined, several fundamental issues are still controversial: Are the motor neurons the first and solely direct targets of ALS? And what is the contribution of non-neuronal cells, if any, to the pathogenesis of ALS?
Several lines of evidence suggested, for example, that the neurodegenerative action of mutant SOD1 genes operate through a dominant paracrine activity that emanates from non-neuronal tissues. The obvious loss of motor neurons in the spinal cord initially focused attention on how mutant SOD1 might act within motor neurons to provoke neuronal degeneration and death. However, the mutant gene products are expressed widely, which raises the possibility that the toxicity might result from the action of mutant SOD1 protein in non-neuronal cells.
Thus, several recent lines of evidence (including our recent studies) support the redefinition of ALS as a multi-systemic disease in which alterations in structural, physiological, and metabolic parameters in different cell types (motor neurons, glia, and muscle) may act synergistically to exacerbate the pathology.
Therefore, it is very important to develop appropriate tools for elucidating the role of different tissues, including muscle, in ALS pathogenesis, and for developing drugs to counter the effects of this disease.
University of Strasbourg
This is a very sound paper, and the electrophysiology is well done, as expected from this group. The information is more technical rather than adding new data on ALS specifically, but it is a real breakthrough. They compare well-known differentiated myoblasts to their oocyte “microtransplantation" approach that they present here. They indeed show some (minor) differences in the acetylcholine receptor properties (showing that differentiated myoblasts don't retain original—here ALS—features or cell traits). With this new technique (microtransplantation into Xenopus oocytes), we now have access to (more) original disease traits that are retained. Despite the lack of biological data, this work clearly opens new possibilities to analyze (electrophysiologically or with other approaches) biological material with fewer artifacts, for example, those due to differentiation or a long in-vitro process.
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