**Author details**

be evaluated to which extent these cells recapitulate neurodegenerative disease phenotypes, although a first report from fibroblast derived neurons from a familial Alzheimer's patient

In summary, the technique of reprogramming holds great promises in terms of disease mod‐ eling and unraveling of underlying mechanisms of sporadic neurodegenerative diseases such as ALS. Despite the current confusion due to the various methods used to generate the lines, the observed clonal variations as well as the limited reflection of disease phenotypes, the field has advanced with tremendous speed if one considers that the first report about reprogramming of mouse fibroblasts was published only 6 years ago. With combined efforts and improved methods, a better understanding and control of the reprogramming mecha‐ nisms can be achieved, thereby facilitating the interpretation and usage of the generated

**6. Future trends in modeling ALS and discovering new therapies**

phrenia [80], Rett syndrome [95] and ALS [14].

The recent remarkable advancement in the cell biology field that adult fibroblasts can be re‐ programmed to virtually originate all cell types have created a unique opportunity to model neurological disorders *in vitro*. iPS technology has already been applied to several neurode‐ generative conditions, from Alzheimer's disease [93] to Down syndrome [94], as well schizo‐

Although a large number of iPS cell lines from patients affected by various diseases have been made commercially available, it is still not clear how robustly these recapitulate the characteristics specific of each disease. Although the promises of iPS technology are to lead to high-throughput screenings to find new efficacious therapeutic targets, they are subject to some main limitations that have already been addressed in other sections of this book chap‐ ter. It is, therefore, of paramount importance that the properties of the differentiated cells are well characterized and it is verified that they are representative of the disease they are

However, some promising results have been obtained from a very recent study suggesting that iPS-derived motor neurons originated from patients carrying TDP-43 mutations display abnormalities typical of TDP-43 proteinopathy. These cells display elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival, and increased vulnerability to inhibition of phosphatidylinositol 3-kinase (PI3K) pathway [78] as well as shorter neurites and TDP-43 cytoplasmic aggregates [82]. These parameters can be used as readout for highthroughput drug screenings as well as short hairpin RNA (shRNA) library screenings. In‐ deed, Egawa and colleagues performed microarray analysis on iPS-derived motor neurons transduced with lentivirus expressing green fluorescent protein (GFP) under the control of the HB9 promoter. Based on the results obtained from gene expression analysis, the authors tested 4 drugs known to modulate transcription through histone modification and RNA splicing. Using the high content imaging analyzer InCell 6000, Egawa and colleagues found

seem promising [92].

174 Current Advances in Amyotrophic Lateral Sclerosis

cells.

modeling.

Laura Ferraiuolo\* , Kathrin Meyer and Brian Kaspar

Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
