Cross-study GSEA outmatched the list comparisons and revealed interesting commonly affected pathways in MS, EAE, TMEV-IDD, and TNFtg including coagulation which represents a promising target for future studies. For unknown reasons we observed a lack of the anticipated transcriptional changes suggestive of oligodendrocyte dystrophy and Ergosterol apoptosis in TNFtg. Further microarray studies in toxin-induced animal models like cuprizone or ethidium bromide are needed to engage the hypothesis of multiple etiology and pathogenesis in MS on the transcriptional level. TAR DNA-binding protein 43 is a multifunctional nuclear protein initially described as a transcription factor, but later found to be also involved in regulation of RNA splicing, microRNA processing, mRNA transport, stability and translation. In 2006 it was reported, for the first time, that TDP-43 is the main component of the ubiquitin-positive, tau-negative and asynuclein-negative protein inclusions accumulating in the frontotemporal cortex and hippocampus of the brain and in the motor neurons of the LOUREIRIN-B spinal cord of patients suffering from frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. TDP-43 inclusions are also found in other neurodegenerative conditions, such as Alzheimer’s disease and Parkinson’s disease, as well as in inclusion body myositis and myofibrillar myopathy. However, the presence of other protein inclusions and clinical manifestations in all such conditions, and the observation that all TDP-43 mutations so far discovered are only associated with familial ALS and FTLDU, suggest that TDP-43 aggregation is rather a secondary process in this group of neurodegenerative and muscle diseases. Pathological TDP-43 aggregation is associated with a dislocation of this protein from the nucleus, where the protein normally resides and plays its functions, to the cytoplasm, where the inclusions accumulate. In such cytoplasmic inclusions TDP-43 is hyperphosphorylated, ubiquitinated and cleaved to form C-terminal fragments, although in the spinal cord motor neurons the inclusions consist rather of full-length TDP-43. The structure of TDP-43 in the inclusions of ALS and FTLD-U patients is not yet clear and subject of current debate. In particular, it is not yet clear whether TDP-43 inclusions consist of amyloid fibrils or rather another type of protein aggregate. In order to be classified as amyloid, protein aggregates need to comply with three main criteria that are nowadays accepted by investigators from different disciplines, from biophysicists to clinicians: the presence of a fibrillar morphology with the fibrils having a diameter of typically 7�C13 nm, the presence of a cross-b secondary structure and the binding to amyloid-diagnostic dyes like Congo red, thioflavin T and thioflavin S. Spinal cord sections of ALS patients show the presence of TDP-43 positive, 10�C20 nm wide filaments in the absence of CR and ThS binding, thus suggesting a non-amyloid structure. However, a very recent report indicates the presence of a widespread remarkable ThS staining in TDP-43 inclusions present in the lower motor neurons of sporadic ALS cases, suggesting rather an amyloid-like structure. In another very recent report, it was shown that a few TDP-43 inclusions of ALS patients may consist of 10�C20 nm fibrils able to bind ThS, but such features were found only in a small fraction of skein-like inclusions of the spinal cord, with amyloid-like characteristics being absent in most spinal cord skeins and absent altogether in other TDP-43 inclusions of the spinal cord and in all inclusions of the brain. As far as FTLD-U is concerned, TDP-43 inclusions in the brain were found to consist of 15�C20 nm wide filaments.