RNA-binding proteins in neurological disease

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Editorial

RNA-binding proteins in neurological disease

Regulation of RNA metabolism in neurons is remarkablyelaborate, involving alternative splicing and compartmental-ized expression through long distance mRNA trafficking andlocal translation. The complexity of RNA metabolism in thenervous system also appears to create a unique vulnerabilitythat underlies the development of some devastating neuro-logical diseases. It has been long appreciated that disturbanceof RNA metabolism underlies some neurodegenerative dis-eases, including spinal muscular atrophy and certain trinu-cleotide repeat expansions, among others. More recently, thisnotion was brought into sharper focus by a series of seminaldiscoveries. First was the identification of the RNA-bindingprotein (RBP) called TAR DNA-binding protein 43 (TDP-43) asthemajor disease protein in the pathological inclusions foundin amyotrophic lateral sclerosis (ALS) and frontotemporaldementia (FTD). Subsequently, mutations in TDP-43 werefound to account for a small percentage of familial ALS cases,establishing the relevance of TDP-43 to pathogenesis. Shortlyafter the emergence of TDP-43, mutations in a related RBPcalled Fused in Sarcoma (FUS) were found to be causative ofrare cases of ALS, further implicating altered RNAmetabolismas a central feature of these diseases. Most recently, hexanu-cleotide repeat expansion in the non-coding region of thegene C9ORF72 was found to be the most common mutation inboth familial and sporadic forms of ALS/FTD. The moleculardefect in C9ORF72-related ALS/FTD is reminiscent of the tri-and tetra-nucleotide repeat expansions responsible for myo-tonic dystrophy, suggesting that a similar mechanism of RBPsequestration by toxic RNA could be at work.

To capitalize on the rapid series of advances in thisnascent field, a two-day symposium called “RNA-BindingProteins in Neurological Disease” was held on November10–11, 2011 in Washington DC. Approximately 250 scientistsattended the symposium and more than 100 posters werepresented. Tom Maniatis delivered the keynote lecture and 35additional speakers gave presentations relating to the role ofRBPs and perturbed RNA metabolism in neurodegenerativediseases. A subset of these speakers has contributed manu-scripts relating to their research topic for this special issue ofBrain Research.

In 2006, Virginia Lee and colleagues combined biochemicaland immunohistological approaches to identify the majorprotein constituent of ubiquitinated cytoplasmic neuronalinclusions in FTD, which turned out to be TDP-43 and wassubsequently found to be the major constituent of patholog-ical inclusions in ALS as well. This discovery provided strong

evidence that FTD and ALS are different manifestations of aclinicopathological spectrum with a common underlyingetiology. A striking feature of TDP-43 pathology in ALS andFTD is the redistribution of this RBP from its normal nuclearlocalization to dense cytoplasmic inclusions. A key questionthat arises from this observation is whether disease patho-genesis is a consequence of TDP-43 depletion from thenucleus or whether a toxic gain of function of TDP-43 in thecytoplasm is primarily to blame. This special issue containsseveral articles that focus on TDP-43, including its normalfunction and how this is altered in disease. Gene Yeo and DonCleveland and their colleagues discuss in detail the RNAtargets and autoregulation of TDP-43 and how misregulatedRNA processing might contribute to ALS/FTD pathogenesis.Gang Yu and his colleagues summarize our understanding ofthe relationship between TDP-43 and stress granules andpropose two models of TDP-43 aggregate formation. The basisfor TDP-43 aggregation is a topic of great interest and, indeed,in an original research article in this special issue FranciscoBaralle and colleagues provide fresh insights into how specificdiseasemutations in TDP-43 affect its propensity to aggregate.Many studies on TDP-43 rodent models have been publishedduring the last 2 years. Philip Wong and colleagues reviewwhat has been learned from these models as well as theirpotential limitations.

In 2009, mutations in the RBP FUS were found to cause ALS,and FUS pathology was subsequently reported in about 5% ofFTD cases. Curiously, patients with ALS/FTD related to FUSmutations showpathological inclusions of FUS, but not TDP-43.FUS, Ewing's sarcomaprotein (EWS), andTATA-bindingproteinassociated factor 15 (TAF15) are functionally related andconstitute the so-called “FET protein” family. Ian Mackenzieand Manuela Neumann summarize the latest findings on theunique pathological features in FTD and ALS that involve eachof the three FET proteins. As in the case of TDP-43, cellular andanimal models of FUS toxicity have been rapidly established.Much has been learned about the normal function of FUS, thebasis for its toxicity and its relationshipwith TDP-43, and this isthe focus of the review provided by Nicholas Lanson Jr. andUdai Bhan Pandey.

A feature common to most hnRNPs is the presence of a so-called “glycine-rich domain” of unknown function. Mostdisease-causing mutations in TDP-43 and some disease-causing mutations in FUS are found within this domain, whichhas led to particular interest in the properties of this domain.The glycine-rich domain of hnRNPs is rich in uncharged, polar

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amino acids, similar to that observed in the nucleation do-mains found in many yeast prions. This has led to specu-lation that a prion-like aggregation property native to someRBPs may contribute to onset and/or progression of FTD,ALS, and related neurodegenerative diseases. This emergingtheme is insightfully discussed by Oliver King, Aaron Gitler,and James Shorter.

While understanding the roles of TDP-43 and FUS in neuro-degeneration pose important new challenges, much can belearned fromother well-studied RBPs involved in related neuro-degenerative diseases. For instance, loss of function mutationsaffecting the survival of motor neuron-1 (SMN1) gene causesspinal muscular atrophy. Eileen Workman, Stephen Kolb andDaniel Battle discuss the molecular mechanisms of the assem-bly of SMN-dependent small nuclear ribonucleoprotein (snRNP)complexes and how disease mutations may affect pre-mRNAsplicing. In addition to the well-established role of SMN in RNAsplicing, it has more recently been appreciated that SMN1 maycontribute importantly to axonal transport of messenger RNPs(mRNPs),which is the topic of the reviewbyClaudia Fallini, GaryBassell, andWilfreid Rossoll.

One large and expanding class of neurodegenerativediseases is caused by the expansion of microsatellite repeats.Among this class are myotonic dystrophy types 1 and 2,multisystem disorders caused by (CTG)n and (CCTG)n expan-sions, respectively, in non-coding regions of two unrelatedgenes. Gloria Echeverria and Thomas Cooper review theevidence for various possible mechanisms of pathogenesisincluding sequestration of key RBPs by expanded repeats andthe induction of so-called “repeat-associated, non-ATG (RAN)translation.” This important topic is receiving increasedattention in light of the recent discovery of (GGGGCC)nexpansions in C9ORF72 as the basis for a large percentage offamilial and sporadic ALS/FTD. Yujing Li and Peng Jin focus onRNA-mediated neurodegeneration in Fragile X-associatedtremor/ataxia syndrome, a disease caused by CGG repeats in

the 5′ untranslated region of the fragile X mental retardationprotein 1 (FMR1) gene. Loss of FRMP leads to fragile X syn-drome, the most common inherited form of mental retarda-tion. The biological functions of FMRP are further investigatedin an original research article contributed by Daniela Zarnescuand colleagues.

Among the various etiologies of FTD-TDP is the loss offunction mutations affecting the GRN gene resulting inprogranulin haploinsufficiency. Although it is unclear howprogranulin deficiency leads to TDP-43 pathology, restoringprogranulin expression has emerged as an attractive thera-peutic strategy, as discussed in an article by Leonard Petrucelliand colleagues. Another promising avenue for understandingdisease mechanisms and screening potential therapeuticcompounds is induced pluripotent stem cell (iPSCs) technol-ogy, pioneered by Shinya Yamanaka. The utility of thisremarkable new approach in neurodegeneration research isdiscussed by Jernej Ule and colleagues.

In summary, the emergence of altered RBP function in ALS,FTD and related neurodegenerative diseases has resulted in aparadigm shift in the field. There can be no doubt that thepace of insights into the molecular bases for these diseaseshas been accelerated as a consequence, bringing us closer tothe day when meaningful therapies are developed.

Fen-Biao GaoDepartment of Neurology,

University of Massachusetts Medical School, Worcester,MA, 01605, USA

E-mail address: fen-biao.gao@umassmed.edu

J. Paul TaylorDepartment of Developmental Neurobiology,

St. Jude Children's Research Hospital, Memphis, TN 38105, USAE-mail address: jpaul.taylor@stjude.org