Neurodegeneration the RNA way

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Abstract

The expression, processing, transport and activities of both coding and non-coding RNAs play critical roles in normal neuronal function and differentiation. Over the past decade, these same pathways have come under scrutiny as potential contributors to neurodegenerative disease. Here we focus broadly on the roles of RNA and RNA processing in neurodegeneration. We first discuss a set of “RNAopathies”, where non-coding repeat expansions drive pathogenesis through a surprisingly diverse set of mechanisms. We next explore an emerging class of “RNA binding proteinopathies” where redistribution and aggregation of the RNA binding proteins TDP-43 or FUS contribute to a potentially broad range of neurodegenerative disorders. Lastly, we delve into the potential contributions of alterations in both short and long non-coding RNAs to neurodegenerative illness.

Highlights

► RNA-mediated mechanisms play a critical role in neurodegeneration. ► Toxic RNAs sequester RNA-binding proteins and trigger aberrant translation. ► Altered RNA-binding protein activity and distribution drive toxicity in ALS. ► Non-coding RNAs play novel roles in neurodegeneration.

Introduction

As the world population ages over the coming decades, the medical system will face an ever increasing incidence of neurodegenerative disorders. It is estimated that one in 7 people in the US will develop a neurodegenerative disorder in their lifetime, and dementia is now the 6th leading cause of death in the US (Dorsey et al., 2007, Thies and Bleiler, 2011). Neurodegeneration is the broad term used to describe the progressive loss first of neuronal function, then of the neurons themselves. As a central component of many forms of neurodegenerative disease is the presence of protein aggregates, much research to date has focused on protein quality control mechanisms in an effort to understand and possibly treat these disorders (Williams and Paulson, 2008, La Spada and Taylor, 2010, Selkoe, 2011). An emerging avenue of research in neurodegeneration focuses instead on the mechanisms by which RNA and RNA processing contribute to neuronal dysfunction and death. For a subset of diseases, direct mRNA toxicity via a gain of function mechanism has been proposed (Osborne and Thornton, 2006, O’Rourke and Swanson, 2009, Todd and Paulson, 2010). However, for a broader set of disorders, alterations in non-coding RNA, RNA splicing and RNA binding protein activity accompany or drive the neurodegenerative process in novel ways (Gallo et al., 2005, Cooper et al., 2009, Lagier-Tourenne et al., 2010). Moreover, the possibilities for transcriptional control mediated by long non-coding RNAs are just beginning to come to light, suggesting an even more complex mechanism by which disturbances at the RNA level can contribute to degeneration of the nervous system (Wapinski and Chang, 2011).

This review provides a broad summary of the myriad of ways by which both coding and noncoding RNAs and RNA binding proteins contribute to neurodegenerative disease. Our goal is to provide both a topical introduction for the uninitiated, as well as to facilitate cross-talk among researchers within the various subtopics we cover. We believe that there is likely significant and underappreciated overlap across different neurodegenerative disorders in terms of the mechanisms by which RNA contributes to disease pathogenesis, as evidenced by recent studies in ALS and frontotemporal dementia (DeJesus-Hernandez et al., 2011, Renton et al., 2011). Given the breadth of this topic, aspects of our coverage of specific areas are at times limited or superficial. For each subtopic, we have therefore referenced numerous excellent recent reviews that should allow for more in-depth exploration.

Section snippets

Function and processing of RNAs in the central nervous system

To appreciate how alterations in the processing and expression of coding and non-coding RNAs contribute to neurodegeneration, it is important to review recent advances in our understanding of how RNA participates in the regulation of gene expression, RNA processing, and protein translation.

The human transcriptome is made up of both protein coding messenger RNAs (mRNAs) and multiple different classes of non-coding RNAs (ncRNAs), including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small

RNA as a toxic species: the sequestration hypothesis

The concept that RNA itself acts as a primary toxic species in a neurological disorder was first proposed and established for myotonic dystrophy type 1 (DM1). DM1 is the most common adult onset muscular dystrophy and the third most common overall (Philips et al., 1998, Mankodi et al., 2000, Liquori et al., 2001, Kanadia et al., 2003, Wheeler and Thornton, 2007). In addition to skeletal muscle weakness and myotonia, patients with DM1 also have complications related to cardiac function,

TDP-43 and FUS as “RNA binding-proteinopathies”

A major area of advancement in neurodegenerative disease research over the past five years involves the identification of two proteins commonly found in neuronal inclusions: the Tar DNA binding protein of 43 kD (TDP-43) and the Fused in Sarcoma/Translocated in Liposarcoma protein (FUS/TLS) (Lagier-Tourenne and Cleveland, 2009, Buratti and Baralle, 2010, Chen-Plotkin et al., 2010, Gendron et al., 2010, Lagier-Tourenne et al., 2010, Mackenzie et al., 2010). TDP-43 was identified as a component of

MicroRNAs in neurodegeneration

MicroRNAs (miRNAs) are short non-coding RNAs which regulate mRNA stability and translation (Eacker et al., 2009). In addition to direct RNA toxicity and the primary roles of TDP-43 and FUS in neurodegenerative disorders, numerous lines of research now implicate miRNAs and altered miRNA processing in neurodegeneration (Hebert and De Strooper, 2009, Delay and Hebert, 2011, Enciu et al., 2011). Generally, these studies have taken one of two approaches: studying the impact of global miRNA synthesis

The new RNAs on the block: a future role in neurodegeneration?

While miRNAs have been widely studied to date, a number of other important classes of non-coding RNAs have not yet been extensively examined for roles in neurodegeneration. Long non-coding RNAs likely play critical roles in neuronal function and thus might be expected to contribute to neurodegenerative processes (Mercer et al., 2008, Qureshi et al., 2010). Long intergenic non-coding RNAs (lincRNAs) are evolutionarily conserved sequences that are transcribed, spliced and polyadenylated in a

Concluding remarks

This review has addressed but a few of the myriad of ways in which RNA and RNA processing might contribute to the pathogenesis of neurodegenerative disease. mRNAs that contain nucleotide repeat sequences can directly elicit neuronal dysfunction by binding to and sequestering critical proteins, preventing them from their normal functions. RNA binding proteins themselves, such as TDP-43 and FUS/TLS, can be mutated or inappropriately localized within neurons and thus contribute to

Acknowledgements

This work was supported by NIH K08NS069809 and the Bucky and Patti Harris Professorship to PK Todd and the Systems and Integrative Biology Training Grant to AJ Renoux.

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