Rodent Models of TDP43 Proteinopathy Investigati

Authors: Tania F Gendron Leonard Petrucelli

Publish Date: 2011/08/03

Volume: 45, Issue: 3, Pages: 486-

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Abstract

Since the identification of phosphorylated and truncated transactive response DNAbinding protein 43 TDP43 as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinpositive inclusions much effort has been directed towards ascertaining how TDP43 contributes to the pathogenesis of disease As with other protein misfolding disorders TDP43mediated neuronal death is likely caused by both a toxic gain and loss of TDP43 function Indeed the presence of cytoplasmic TDP43 inclusions is associated with loss of nuclear TDP43 Moreover posttranslational modifications of TDP43 including phosphorylation ubiquitination and cleavage into Cterminal fragments may bestow toxic properties upon TDP43 and cause TDP43 dysfunction However the exact neurotoxic TDP43 species remain unclear as do the mechanisms by which they cause neurotoxicity Additionally given our incomplete understanding of the roles of TDP43 both in the nucleus and the cytoplasm it is difficult to truly appreciate the detrimental consequences of aberrant TDP43 function The development of TDP43 transgenic animal models is expected to narrow these gaps in our knowledge The aim of this review is to highlight the key findings emerging from TDP43 transgenic animal models and the insight they provide into the mechanisms driving TDP43mediated neurodegenerationMany neurodegenerative diseases are characterized by the misfolding and aggregation of proteins into intracellular inclusions The transactive response DNAbinding protein 43 TDP43 was recognized as one such protein when in 2006 it was identified as a primary component of ubiquitinated inclusions in the most frequent form of frontotemporal lobar degeneration FTLD and in most cases of amyotrophic lateral sclerosis ALS Arai et al 2006 Neumann et al 2006Frontotemporal dementia FTD the third most common cause of dementia in industrialized countries after Alzheimer’s disease AD and dementia with Lewy bodies Neary et al 1998 Snowden et al 2002 encompasses a heterogeneous group of neurodegenerative disorders distinguished clinically by abnormalities in behavior language and personality Seelaar et al 2011 The most common clinical syndrome behavioralvariant FTD is associated with disinhibition and social inappropriateness Other clinical syndromes include progressive nonfluent aphasia and semantic dementia In some instances FTD patients display movement abnormalities with clinical features of motor neuron disease MND resembling ALS FTLD is the neuropathologic substrate of FTD being characterized by the predominant atrophy of the frontal and temporal lobes and the presence of proteinaceous inclusions in neurons and glia It is broadly divided into cases with taupositive inclusions FTLDtau and those with taunegative ubiquitinpositive inclusions FTLDU The ubiquitinated protein in most FTLDU cases is TDP43 and these are consequently classified as FTLD–TDPALS is characterized by the progressive degeneration of motor neurons in the cerebral cortex upper motor neurons brain stem and spinal cord lower motor neurons resulting in muscle weakness atrophy and spasticity Additionally ALS can involve several nonmotor systems and subcortical structures and there is evidence of cognitive deficits in a considerable number of ALS patients Lowe 1994 Abe et al 1997 Frank et al 1997 LomenHoerth et al 2003 Ringholz et al 2005 Murphy et al 2007 Cytoplasmic ubiquitinpositive inclusions are present in lower motor neurons and less frequently upper motor neurons Leigh et al 1991 Ince et al 1998 In cases of ALS with dementia and in some patients with minor cognitive changes ubiquitinpositive inclusions are also present in other brain regions including the extramotor neocortex and hippocampus Okamoto et al 1991 Wightman et al 1992 Mackenzie and Feldman 2005 Geser et al 2008a It is now well established that TDP43 is the primary component in glial and neuronal inclusions present in most ALS patients with the exception of those with familial ALS caused by mutations in Cu/Zn superoxide dismutase SOD1 Arai et al 2006 Neumann et al 2006 Cairns et al 2007 Davidson et al 2007 Grossman et al 2007 Higashi et al 2007a Mackenzie et al 2007 Neumann et al 2007 Seelaar et al 2007 Tan et al 2007 Hatanpaa et al 2008 Pikkarainen et al 2008 Josephs et al 2009 Based on the significant overlap of clinical and pathological features among FTLDTDP with or without MND and ALSTDP with or without dementia it has been suggested that these TDP43 proteinopathies are situated at points along one continuous clinicopathological spectrum of multisystem neurodegenerative diseases Geser et al 2010In addition to ALSTDP and FTLDTDP TDP43 pathology has been observed to a variable extent in other neurodegenerative disorders including Lewy body disease Higashi et al 2007b NakashimaYasuda et al 2007 parkinsonism–dementia complex of Guam Hasegawa et al 2007 Geser et al 2008b corticobasal degeneration Arai et al 2006 Uryu et al 2008 Pick’s disease Arai et al 2006 AD Arai et al 2006 AmadorOrtiz et al 2007 Higashi et al 2007b Uryu et al 2008 Perry syndrome Wider et al 2009 and hippocampal sclerosis AmadorOrtiz et al 2007 Cairns et al 2007 Whether the presence of TDP43 pathology in these diseases indicates that TDP43 contributes to their development or progression has yet to be determined It is interesting to note however that the presence of TDP43 pathology in AD is associated with greater brain atrophy and more severe clinical deficits Josephs et al 2008 Studies also suggest that amyloidβ triggers TDP43 pathology ie TDP43 phosphorylation cleavage and accumulation in the cytosol in mouse models of AD Caccamo et al 2010 Herman et al 2011 while TDP43 overexpression heightens αsynuclein toxicity to dopaminergic neurons in transgenic mice Tian et al 2011The identification of numerous missense mutations in TARDBP the gene encoding TDP43 in sporadic and familial ALS as well as in patients with FTD provides evidence of a direct link between TDP43 abnormalities and neurodegeneration Gitcho et al 2008 Kabashi et al 2008 Kuhnlein et al 2008 Rutherford et al 2008 Sreedharan et al 2008 Van Deerlin et al 2008 Yokoseki et al 2008 Benajiba et al 2009 Borroni et al 2009 Corrado et al 2009 Daoud et al 2009 Del Bo et al 2009 Gitcho et al 2009 Kovacs et al 2009 Lemmens et al 2009 As with other protein misfolding diseases TDP43mediated neuronal death in ALSTDP and FTLDTDP is likely caused by multiple pathways involving a combination of toxic gain and loss of TDP43 function The sequestration of TDP43 from the nucleus to cytoplasmic inclusions is expected to result in loss of TDP43 function The inclusions themselves may be neurotoxic merely inert byproducts or a protective mechanism used by cells to sequester harmful TDP43 species Additionally phosphorylation ubiquitination and cleavage of TDP43 into Cterminal TDP43 fragments posttranslational modifications observed only in disease may both bestow toxic properties upon TDP43 and cause TDP43 dysfunctionAs our knowledge of the normal function of TDP43 continues to grow so too shall our understanding of the mechanisms that drive TDP43mediated neurodegeneration TDP43 an RNA/DNA binding protein is among the class of heteregeneous riobonucleoproteins and is believed to regulate multiple steps of RNA metabolism including transcription splicing mRNA transport and microRNA biosynthesis Buratti and Baralle 2010 Although TDP43 is largely a nuclear protein it does shuttle between the nucleus and cytoplasm in a transcriptiondependent manner and a small proportion of TDP43 is present in the cytoplasm under physiological conditions Ayala et al 2008 Winton et al 2008 This suggests that in addition to its nuclear functions TDP43 may play an important role in the cytoplasm a hypothesis that is strengthened by the findings that the postsynaptic localization of TDP43 in the form of RNA granules is enhanced following depolarization of primary hippocampal neurons Wang et al 2008a and that TDP43 relocates to cytoplasmic stress granules in response to harmful stimuli in cell and animal models Colombrita et al 2009 Moisse et al 2009a b Freibaum et al 2010 LiuYesucevitz et al 2010 Dewey et al 2011 McDonald et al 2011 Together these findings suggest that TDP43 regulates synaptic plasticity by controlling the transport and splicing of synaptic mRNAs and assists in the physiological response to neuronal injuryRecently developed rodent TDP43 transgenic models are expected to serve as valuable tools to better understand the role of TDP43 within the central nervous system as well as provide insight on the mechanisms by which TDP43 contributes to the development and progression of neurodegeneration Wegorzewska et al 2009 Shan et al 2010 Stallings et al 2010 Tsai et al 2010 Wils et al 2010 Xu et al 2010 Zhou et al 2010 Igaz et al 2011 Tian et al 2011 The aim of this review is to highlight key findings emerging from TDP43 transgenic animals as well as some of the many questions in need of further investigation

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