Abstract
Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by degeneration of the fronto temporal lobes and abnormal protein inclusions. It exhibits a broad clinicopathological spectrum and has been linked to mutations in seven different genes. We will provide a picture, which connects the products of these genes, albeit diverse in nature and function, in a network. Despite the paucity of information available for some of these genes, we believe that RNA processing and post-transcriptional regulation of gene expression might constitute a common theme in the network. Recent studies have unraveled the role of mutations affecting the functions of RNA binding proteins and regulation of microRNAs. This review will combine all the recent findings on genes involved in the pathogenesis of FTD, highlighting the importance of a common network of interactions in order to study and decipher the heterogeneous clinical manifestations associated with FTD. This approach could be helpful for the research of potential therapeutic strategies.
Highlights
All the information reported in the table is derived from a cumulative study of the literature and the database: http://www.molgen.ua.ac.be/ADMutations/default.cfm?MT=0&ML=2& Page=Frontotemporal dementia (FTD)
In this review we describe the different genes involved in FTD, focusing on their possible interactions, in order to identify a common network of their combined regulations
We believe that the RNA mediated regulation plays a key role in the unique integration of all the known genes involved in FTD
Summary
Despite 90% of the human genome being transcribed to RNA, only 1.2% of genomic sequence is protein-coding, indicating that a huge proportion of non-coding RNAs (ncRNAs) are likely to participate in a number of physiological processes in cell types, including neurons (Lander et al, 2001; Birney et al, 2007; Wilhelm et al, 2008; Clark et al, 2011). The pre-mRNAs undergoes alternative splicing producing mature messenger RNAs (mRNAs) which are expressed in specific tissues and cell types in different stages of development These mRNAs associate with the ribosomal machinery to be translated into proteins in the cytoplasm. It is estimated that one in seven people in the US might develop a neurodegenerative disorder in their lifetime, with dementia being one of the leading causes of death in US (Thies and Bleiler, 2011) Though this broad spectrum of disorders has been studied based on protein aggregation and research has been focusing on protein functions and alterations, emerging avenues in research unravels the role of RNA and RNA processing in contributing to neurodegeneration (Belzil et al, 2013). Structure TDP-43 is a 414 amino acids protein (Figure 2A) containing two RNA recognition motifs (RRMs), a glycine-rich low sequence
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