In silico, in vitro, and in vivo approaches to identify molecular players in fragile X tremor and ataxia syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative monogenetic disorder affecting carriers of premutation (PM) forms of the FMR1 gene, resulting in a progressive development of tremors, ataxia, and neuropsychological problems. This highly disabling disease is quite common in the general population with an estimation of about 20 million PM carriers worldwide. The chances of developing FXTAS increase dramatically with age, with about 45% of male carriers over the age of 50 being affected. Both the gene and pathogenic trigger, a mutant expansion of CGG RNA, causing FXTAS are known. This makes it an interesting disease to develop targeted therapeutic interventions for. Yet, no such interventions are available at this moment. Here we discuss in silico, in vitro, and in vivo approaches and how they have been used to identify the molecular determinants of FXTAS pathology. These approaches have yielded substantial information about FXTAS pathology and, consequently, many markers have emerged to play a key role in understanding the disease mechanism. Integration of the different approaches is expected to provide crucial information about the value of these markers as either therapeutic target or biomarker, essential to monitor therapeutic interventions in the future.The research leading to these results has been supported by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC grant agreement RIBOMYLOME_309545 to GT and ASTRA 855923 to GT, the Spanish Ministry of Science and Innovation (AEI/ERDF, BFU2014-55054-P and BFU2017-86970-P) and the ‘Fundació La Marató de TV3’ (PI043296