Abnormalities of the nucleus and nuclear inclusions in neurodegenerative disease: A work in progress

Department of Pathology, The Ottawa Hospital, University of Ottawa, and Cancer Research Program, The Ottawa Health Research Institute, Ottawa, Canada.
Neuropathology and Applied Neurobiology (Impact Factor: 3.93). 03/2007; 33(1):2-42. DOI: 10.1111/j.1365-2990.2006.00819.x
Source: PubMed


Neurodegenerative diseases are characterized pathologically by the abnormal accumulation of pathogenic protein species within the cell. Several neurodegenerative diseases feature intranuclear protein aggregation in the form of intranuclear inclusion bodies. Studies of these intranuclear inclusions are providing important clues regarding the cellular pathophysiology of these diseases, as exemplified by recent progress in defining the genetic basis of a subset of frontotemporal dementia cases. The precise role of intranuclear inclusion bodies in disease pathogenesis is currently a focus of debate. The present review provides an overview of the diverse family of neurodegenerative diseases in which nuclear inclusions form part of the neuropathological spectrum. In addition, current pathogenetic concepts relevant to these diseases will be reviewed and arguments for and against a protective role for intranuclear inclusions will be presented. The relationship of pathological intranuclear inclusions to functional intranuclear bodies will also be discussed. Finally, by analogy with pathological intranuclear inclusions, I will speculate on the possibility that intranuclear protein aggregation may represent a constitutive cellular protective mechanism occurring in neurons under physiological conditions.

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Available from: John Woulfe, May 21, 2014
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    • ", 2011 ) . The suggestion that nuclear aggregates , containing molecular chaperones and proteasome , can prevent the induction of CD ( Woulfe , 2007 ) was confirmed by the identification of a proteolytic activity in nuclear foci ( Iwata et al . , 2005 ; Rockel et al . "
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    • "Immunohistochemically, the inclusions are immunopositive for ubiquitin (Ub) and ubiquitin-related proteins (SUMO-1 and p62), while inclusions are less often immunolabeled with anti-polyglutamine antibody 1C2 [5] [6] [7] [8] [9] [10]. Recently , it has been reported that NII and GII are immunoreactive for fused in sarcoma (FUS) [11] [12]. "
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    ABSTRACT: Optineurin (OPTN) is a multifunctional protein involved in cellular morphogenesis, vesicle trafficking, maintenance of the Golgi complex, and transcription activation through its interactions with the Rab8, myosin 6 (MYO6), huntingtin. Recently, OPTN immunoreactivity has been reported in intranuclear inclusions in patients with neuronal intranuclear inclusions disease (NIID). Other studies have shown that the RNA-binding protein, fused in sarcoma (FUS), is a component of intranuclear inclusions in NIID. We aimed to investigate the relationship between OPTN, its binding protein MYO6 and FUS in this study. In control subjects, OPTN (C-terminal) (OPTN-C) and MYO6 immunoreactivity was mainly demonstrated in the cytoplasm of neurons. In NIID patients, both neuronal intranuclear inclusions (NII) and glial intranuclear inclusions (GII) were immunopositive for MYO6 as well as OPTN-C. However, the intensity of OPTN-C immunostaining of the neuronal cytoplasm with and without NII was less than that of the control subjects. Double immunofluorescence staining for OPTN-C, ubiquitin (Ub), p62 and FUS revealed co-localization of these proteins within NII. Moreover, Ub positive inclusions were co-localized with MYO6. The percentage of co-localization of Ub with OPTN-C, FUS or MYO6 in NII was 100%, 52% and 92%, respectively. Ultrastructurally, the inclusions consisted of thin and thick filaments. Both filaments were immunopositive for Ub and OPTN-C. These findings suggest that OPTN plays a central role in the disease pathogenesis, and that OPTN may be a major component of NII.
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    • "It is well established that exposed hydrophobicity can lead to deleterious protein aggregation (Chiti, 2006). The nucleus in particular is highly susceptible to aggregation, as evidenced by the many human disorders associated with nuclear aggregation (Woulfe, 2007). From an evolutionary perspective, it is not surprising then that exposed hydrophobicity is the specific structural abnormality recognized by San1. "
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