View Open Access Nuclear Accumulation of Polyglutamine Disease Proteins and Neuropathology Lauren S Havel, Shihua Li and Xiao-Jiang Li*

Molecular Brain BioMed Central Review Open Access Nuclear accumulation of polyglutamine disease proteins and neuropathology Lauren S Havel, Shihua Li and Xiao-Jiang Li* Address: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA Email: Lauren S Havel - [email protected]; Shihua Li - [email protected]; Xiao-Jiang Li* - [email protected] * Corresponding author Published: 3 July 2009 Received: 24 June 2009 Accepted: 3 July 2009 Molecular Brain 2009, 2:21 doi:10.1186/1756-6606-2-21 This article is available from: http://www.molecularbrain.com/content/2/1/21 © 2009 Havel et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract There are nine inherited neurodegenerative disorders caused by polyglutamine (polyQ) expansion in various disease proteins. Although these polyglutamine proteins have different functions and are localized in different subcellular regions, all the polyQ diseases share a common pathological feature: the nuclear accumulation of polyQ disease proteins and the formation of inclusions. The nuclear accumulation of polyQ proteins in turn leads to gene transcriptional dysregulation and neuropathology. Here we will discuss potential mechanisms behind the nuclear accumulation of mutant polyQ proteins, since an understanding of how polyQ proteins accumulate in the nucleus could help elucidate the pathogenesis of these diseases and develop their treatment. There are nine inherited neurodegenerative disorders, expanded proteins. Mutant polyQ proteins in the nucleus including Huntington's disease (HD), dentatorubral-pal- can abnormally interact with nuclear proteins, such as lidoluysian atrophy (DRPLA), spinal bulbar muscular transcription factors, leading to transcriptional dysregula- atrophy (SBMA), and the spinocerebellar ataxias (SCA) tion [2]. The preferential accumulation of mutant polyQ 1,2,3,6,7 and 17, which are caused by a polyglutamine proteins in neuronal nuclei may be associated with the (polyQ) expansion in their respective disease proteins [1]. selective neuropathology seen in polyQ diseases. Thus, it The polyQ domain is encoded by polymorphic CAG is important to understand how polyQ expansions can repeats that are expanded in polyQ diseases. For example, cause the accumulation of polyQ proteins in neuronal in Huntington's disease the polyQ domain is in the N-ter- nuclei. Such an understanding would tell us much about minal region of the HD protein, huntingtin (htt), and its the selective neuropathology of polyQ diseases and also expansion to more than 37 glutamines leads to the neuro- help us develop effective therapeutics for these diseases. In logical symptoms of HD. All the polyglutamine disorders this review, we will discuss the potential mechanisms share several common pathological features, including underlying the accumulation of polyQ-expanded proteins the nuclear accumulation and aggregation of the disease in neuronal nuclei. proteins. Neuronal nuclear inclusions are considered to be a histopathological hallmark of the polyQ diseases and Nuclear accumulation of mutant polyglutamine are even observed in disease brains in which normal proteins polyQ proteins are predominantly expressed in the cyto- In all polyQ diseases, the disease proteins are ubiqui- plasm. Although the role of nuclear inclusions in pathol- tously expressed; however, cell loss is restricted to the ogy is not fully understood, what is clear is that the brain cells of polyQ disease patients. The context of the inclusions result from the nuclear accumulation of polyQ- polyQ proteins and their interacting proteins may deter- Page 1 of 7 (page number not for citation purposes) Molecular Brain 2009, 2:21 http://www.molecularbrain.com/content/2/1/21 mine the selective neuronal loss seen in distinct brain [3,8-10]. These findings suggest that polyQ protein depos- regions in the different polyQ diseases (Table 1). Also, the its are targeted by cellular clearing systems. PolyQ inclu- selective neuropathology appears to be associated with sions are likely to be compact structures consisting the preferential accumulation of expanded polyQ pro- primarily of the polyQ protein itself, since expanded teins in neuronal cells, as the presence of nuclear polyQ polyQ repeats can cause self-association of polyQ pep- proteins is evident in all polyQ disease brains. A prime tides, leading to various forms of the proteins with differ- example of this is that htt, which is normally distributed ent conformations [11]. Examination of the brains of HD in the cytoplasm, can accumulate in the nucleus when its patients indicates that only truncated N-terminal htt frag- polyQ tract is expanded. Immunohistochemical data ments with an expanded polyQ tract are capable of form- from the brains of HD patients reveal the presence of ing nuclear inclusions, as these nuclear inclusions can nuclear htt inclusions in the affected brain regions of both only be labeled by antibodies against the N-terminal, but juvenile and adult patients [3,4]. Patients with other not the internal or C-terminal, region of htt [3,4]. Western polyQ diseases, such as SCA1, SCA3, SCA7, SCA17, blot analysis of HD mouse models that express full-length DPRLA, and SBMA, also show nuclear polyQ inclusions in mutant htt reveals the presence of a number of N-terminal the affected brain regions [1]. Even in the brains of fragments of various sizes [12-14]. Cellular models of HD patients with SCA2 and SCA6, which are caused by a have revealed a number of htt fragments containing the polyQ expansion in the cytoplasmic proteins ataxin-2 and polyQ tract and various proteolytic cleavage sites, includ- ataxin-6, respectively, there is evidence for the presence of ing those for caspase-3, caspase-6, and calpains [15-19]. polyQ inclusions in the nuclei of neuronal cells [5,6]. Nonetheless, which fragments can accumulate in the Moreover, linking an expanded polyQ repeat to the cyto- nucleus and how they contribute to neuropathology plasmic protein Hprt results in the formation of nuclear remain to be investigated. Despite these unanswered polyQ inclusions in the brains of transgenic mice [7]. questions, we know that the presence of N-terminal htt Thus, despite different subcellular localizations of the fragments in HD mouse brains can be detected as early as normal polyQ proteins, mutant proteins with their two months prior to the obvious neurological phenotype, expanded polyQ repeats commonly form nuclear inclu- which does not appear until the age of four to five sions or accumulate in the nucleus; such a common fea- months, indicating that the generation and accumulation ture could be associated with the selective of N-terminal htt precede neurological symptoms [13]. neuropathology of polyQ diseases. The fact that small htt fragments form nuclear inclusions PolyQ inclusions in the nucleus are colocalized with ubiq- suggests that a shorter peptide with a larger polyQ tract uitin, proteasome components, and heat shock proteins tends to misfold and aggregate more rapidly. In other Table 1: A summary of the nine inherited polyglutamine repeat disorders. Disease Disease protein Normal subcellular localization Affected brain regions Huntington's disease (HD) Huntingtin (htt) Cytoplasm Striatum and cortex Spinocerebellar ataxia 1 (SCA1) Ataxin-1 Nuclear and cytoplasmic Cerebellum Spinocerebellar ataxia 2 (SCA2) Ataxin-2 Cytoplasmic Cerebellar Purkinje cells Spinocerebellar ataxia 3 (SCA3) Ataxin-3 Nuclear and cytoplasmic Ventral pons and substantia nigra Dentatorubral-pallidoluysian atrophy Atrophin-1 Nuclear and cytoplasmic Cerebral cortex (DRPLA) Spinocerebellar ataxia 6 (SCA6) Ataxin-6 Membrane associated Cerebellar Purkinje cells Spinocerebellar ataxia 7 (SCA7) Ataxin-7 Nuclear and cytoplasmic Cerebellar Purkinje cells, brain stem, spinal cord Spinal and bulbar muscular atrophy Androgen receptor (AR) Nuclear and cytoplasmic Motor neurons (SBMA) Spinocerebellar ataxia 17 (SCA17) TBP Nuclear Cerebellar Purkinje cells Included are the polyQ proteins, their normal subcellular localization, and affected brain regions. Page 2 of 7 (page number not for citation purposes) Molecular Brain 2009, 2:21 http://www.molecularbrain.com/content/2/1/21 polyQ diseases, it is also evident that shorter polyQ pro- brain mRNAs from various polyQ mouse models have teins are prone to misfolding and aggregation. For exam- revealed some overlap in the expression changes induced ple, western blot analysis of a transgenic mouse model of by the different polyQ disease proteins. For example, DRPLA showed the presence of a small N-terminal frag- comparing gene expression profiles of HD mouse models ment of atrophin-1 [20,21]. Similarly, brain samples from that express exon 1 mutant htt (R6/2) and full-length SCA3 patients as well as mice transgenic for full-length mutant htt shows no discernable differences between the ataxin-3 with 71Q showed the production of a C-terminal full-length and fragment models, despite the delayed truncated fragment with the expanded polyQ domain changes in full-length htt mouse brains, suggesting that N- [22]. Furthermore, the production of small polyQ protein terminal fragments of mutant htt are the major patho- fragments is found to be required for aggregation [23], genic form to induce altered gene transcription [38].

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