TDP-43 and FUS in ALS/FTLD

Abstract

As often happens in science, the discovery in 2006–2009 that TDP-43 and FUS proteins were involved in the pathogenesis of amyotrophic lateral sclerosis (ALS)/frontotemporal lobar degeneration (FTLD)1–3 proved to be a blessing and a curse. A blessing, because the unexpected appearance of these novel proteins held the promise of answering many questions that previous research could not; and a curse, because their discovery introduced yet another layer of complexity to the numerous and sometimes conflicting factors that contribute to a neurodegenerative process.4 To make matters worse, at the time of these discoveries the normal cellular functions of the TDP-43 and FUS proteins were largely unknown.5 This, in turn, hindered the prediction of the pathologic consequences of altered localization or level of expression in the CNS of affected individuals. Nonetheless, that both proteins belong to the hnRNP family of nuclear factors immediately suggested that alterations of RNA metabolism may be the cause of neurodegeneration. Research in the past 5 years substantially confirmed this hypothesis; different facets of RNA metabolism have taken center stage to explain most but not all aspects of neurodegeneration in ALS/FTLD.6–8 The wealth of new published data are now beginning to allow us to fit the experimental observations into a coherent picture.