**Author details**

multitude of cellular processes, such as vesicle transport and protein degradation. In accord‐ ance with literature studies, *VCP* mutations represent one of the major genetic causes of frontotemporal dementia but, recently, a specific mutation in this gene (p.R191Q) has been detected in some cases of FALS [55]. In our analysis, we observed the differential expression of *VCP* in SALS patients (**Figure 5b**). Moreover, several studies have highlighted the existence of a link between alterations in VCP functionality and the toxic gain of function of full-length TDP-43 [56]. The latter is a DNA/RNA binding protein, involved in several processes, includ‐ ing transcription, pre-mRNA splicing, mRNA stability, and mRNA transport [57]. Because of various types of insults, such as dysregulation in calcium homeostasis and oxidative damage, TDP-43 can migrate from the nucleus to the cytoplasm which can cause sequestration of RNA stress granule as well as a loss or gain of splicing functions. Although several studies have focused their attention on the role of TDP-43 in ALS etiopathogenesis, additional investigations are needed. Recent literature data showed the presence of aberrant nuclear or cytoplasmic TDP-43 inclusions in the nervous tissue of ALS patients [58]. It is thus evident that the pharmacological modulation of VCP may represent a promising strategy for ALS treatment, also through the reduction of TDP-43-mediated motor neuron toxicity. Some VCP inhibitors (Vesnarinone and Xanthohumol) have, in fact, demonstrated how to prevent neuronal death

and inflammatory processes occurring in diverse neurological conditions [9].

ALS is a fatal neurodegenerative disease characterized by the influence of diverse mechanisms that interacting among each other promote the development and progression of the disease. Despite intensive research, ALS is still incurable and the only approved drug, Riluzole, conveys only modest benefits to patients. This clinical failure may be mainly due to the actual classification of ALS diseases, which is mainly based on clinical observation of symptoms and physical signs and does not take into account the complexity and heterogeneity of molecular

The advent of high-throughput techniques in the biomedical sciences has provided a frame‐ work for developing a new, more accurate, and refined "molecular taxonomy" of human diseases that implies the use of molecular data to classify patients into distinct subgroups with differing diagnostic, prognostic, or therapeutic implications. In our previous work, we used unsupervised hierarchical clustering to identify two subgroups of SALS patients, characterized by their gene expression pattern, and revealed new clues to pathogenesis and potential

We argue that, as it is already happening in the genomic cancer field, our genomic analysis in combination with other "omics" data will complement and augment existing phenotypic information, providing a much deeper understanding of etiopathogenic mechanisms, which may have been masked by considering SALS as a single entity, and facilitating the develop‐

ment of a more precise diagnosis and individualized treatments for ALS patients.

**5. Conclusion**

250 Update on Amyotrophic Lateral Sclerosis

therapeutic targets.

pathogenic mechanisms underlying ALS.

Giovanna Morello, Francesca Luisa Conforti, Antonio Gianmaria Spampinato and Sebastiano Cavallaro\*

\*Address all correspondence to: sebastiano.cavallaro@cnr.it

Institute of Neurological Sciences, Italian National Research Council, Catania and Mangone (CS), Italy
