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Role of BRCA1 in Neuronal Death in Alzheimer’s Disease M. Wezyk* and C. Zekanowski Laboratory of Neurogenetics, Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland ABSTRACT: Oxidative damage of DNA has recently been indicated as one of the strong pathogenic agent in Alzheimer’s disease (AD). Oxidative stress induces numerous signaling pathways, including DNA damage response (DDR), associated with the breast cancer type 1 susceptibility protein (BRCA1) protein, known to date from numerous reports in the cancer field. In this Viewpoint, we discuss the latest discoveries related to the role of BRCA1 in the death of neurons in AD. We underline the role of BRCA1 in the development of neurons and speculate on the consequences of BRCA1 dysfunction in the dying brain. In general, this Viewpoint is in a line with several recent reports on the processes and players common at the molecular and genetic level for neurodegenerative and cancerous diseases. KEYWORDS: Alzheimer’s disease, BRCA1, oxidative stress, DNA damage response
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(1) an N-terminal RING (really interesting new gene) finger domain, interacting with BARD1 (BRCA1-associated RING domain protein 1) and playing a key role in the ubiquitination pathway, (2) the BRCT (BRCA1 C′ terminus) domain characteristic for a family of evolutionarily related proteins involved in cell cycle regulation upon DNA damage, and (3) a protein binding site-rich region encoded by exons 11−13. There are isoforms of BRCA1 missing exon 11. The BRCA1Δex11 isoform has nucleotides from 905 to 4215 excluded. As a consequence of this exclusion, the isoform lacks the NLS (nuclear localization signal). Isoforms lacking the NLS can be transported into the nucleus via an alternative mechanism that requires ubiquitin conjugating enzyme E2. However, under circumstances of disturbed availability of ubiquitin E2 enzymes, the BRCA1-Δex11 isoform becomes exclusively cytoplasmic and might promote pathological processes. BRCA1-Δex11 presence is crucial to DNA damage-induced phosphorylation, cell growth, and senescence with aneuploidy and defective mitotic spindle checkpoint. Overall, BRCA1 isoform-specific gene regulation and a balanced ratio of BRCA1 isoforms is required to maintain normal cell physiology. Indeed, recent neurodevelopmental studies showed that BRCA1-Δex11 isoform knockout mice generated using a CNSspecific Nestin-Cre driver had a reduced brain volume in all brain layers to varying degrees, with a complete absence of layers II−IV and a barely observable layer V.2 This neurodevelopmental study also suggested that BRCA1 might function as a centrosomal factor in establishing the cellular polarity of the neural progenitors through the DNA damage sensor kinase ATM and that loss of BRCA1 induced p53-dependent proapoptotic signaling. This study provided important data on the impact of altered BRCA1 expression levels in neuronal cells, both in proliferating precursors and in mature neurons, where its activity should be completely suppressed under physiological conditions. Accordingly, our studies showed
INTRODUCTION The last three decades have provided numerous observations of increased oxidative damage in post-mortem brains of patients affected by neurodegenerative diseases, including Alzheimer’s disease (AD).1 Oxidative stress induces DNA damage response (DDR) manifested by the activation of ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related) signaling pathways. One of the key players in this process is the breast cancer type 1 susceptibility protein (BRCA1). BRCA1 plays a role in a number of cellular pathways that maintain genomic stability, including DNA damageinduced cell cycle checkpoint (CCC), DNA repair, protein ubiquitination, chromatin remodeling, transcriptional regulation, and apoptosis. Interestingly, BRCA1 is necessary for apoptosis of neural precursors during their asymmetrical divisions, and its activity must be extinguished in mature neurons.2 Nevertheless, our understanding of the role of BRCA1 in the death of neurons is still poor. This also applies to many other BRCA1-related proteins involved in the regulation of the cell cycle and DDR, whose presence has been demonstrated in neurons. Because deregulation of cell cycle as a result of DDR may be crucial for neurodegeneration, our knowledge of the neuronal functions of such proteins as BRCA1 should be deepened. Accordingly, several recent studies, including ours, have highlighted the role of BRCA1 and its functional network in the pathology of Alzheimer’s disease.3−5 Therefore, we propose that BRCA1 may be one of the major players in neurodegeneration in AD. We suggest that dysfunction of players such as BRCA1 may occur much earlier than known pathological factors in AD, for example, β-amyloid (Aβ).
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BRCA1 IN BRAIN DEVELOPMENT The BRCA1 tumor suppressor gene codes for a 220 kDa nuclear phosphoprotein that is involved in many cellular processes, such as cell cycle checkpoint control, DNA damage recognition and repair, apoptosis, the ubiquitin−proteasome pathway, and transcriptional regulation. The multifunctionality of BRCA1 is a result of its modular architecture, as it includes © XXXX American Chemical Society
Received: March 31, 2018 Accepted: April 3, 2018
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DOI: 10.1021/acschemneuro.8b00149 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
Figure 1. Proposed dual mechanism of action of overactive BRCA1 in Alzheimer’s disease (AD) iPSC-derived neurons. Immunocytochemical imaging reveals an enhanced colocalization of BRCA1 with PS1 (A) and BRCA1 with β-amyloid (Aβ) (B) in AD-derived iPSC-derived neurons. BRCA1 phosphorylated at Ser1524, cytosolic-relocalized isoform BRCA1-Δex11, and BRCA1 in a complex with BARD1 are overexpressed in ADderived iPSC (C, I). BRCA1 can affect processing of presenilin 1 (PS1), likely by ubiquitination, contributing to the pathology of Aβ (I, II, IV) or affect genomic stability manifested by enhanced DNA damage response (DDR) (I, II, III) marked by a recruitment of γH2AX (IIIa) and contribute to the cell cycle re-entry of postmitotic neurons by activation of the Cdc25C phosphatase (IIIb) upon DDR induction (I−III). Altered processing of PS1 (IVa) might result in abnormal cleavage of APP (IVb) and overproduction of Aβ (see ref 3).
proteins. The presence of BRCA1 is indicative of cell cycle changes and DNA damage, both of which are pathogenic changes in AD. BRCA1 as a RING heterodimer with BARD1 provides E3 ubiquitin ligase activity. The BRCA1/BARD1 ubiquitin ligase activity has been implicated in the ubiquitination of γ-tubulin in the cytosol crucial for centrosomal concentration of proteins in the cell cycle, as mentioned in the above paragraph. The upregulation of BRCA1/BARD1 could adversely affect centrosomal cytoskeleton-organizing center of microtubule nucleation and anchoring in neurons and therefore destabilize neuronal polarization and intracellular transport. Cells devoid of BRCA1 undergo centrosome amplification and lose checkpoints in G2. Consequently, BRCA1-deficient cells accumulate cytogenetic aberrations, such as chromosomal translocations, and display aneuploidy. On the other hand, overexpression of BRCA1 was found to sensitize various cancer cells for prodeath treatments, such as those with lovastatin via regulation of the cyclin D1−CDK4− p21WAF1/CIP1 pathway In neurons, the situation might be unique. Upon oxidative stress, neurons may turn on the progression of cell cycle in order to survive, which is further followed by mitotic catastrophe and ultimate apoptotic signaling. Since BRCA1 is involved in DNA repair, suspension of the cell cycle, and apoptosis, the prevalence of BRCA1 increases as AD and neurodegeneration progresses. Indeed, the expression of the BRCA1 protein may be activated early in the progression of AD. This is consistent with the hypothesis that changes in cell cycle take place very early in the progression of the disease,
abundant expression of BRCA1-Δex11 under pathological conditions in AD neurons. This effect was more pronounced upon DDR induced with doxorubicin.3 What is more, we found an increased level of BARD1−BRCA1 complex, which is crucial for ubiquitin E3 ligase activity of BRCA1. Under pathological conditions BRCA1−BARD1 ubiquitin ligase activity has been implicated in the ubiquitination of γ-tubulin in the cytosol, a process crucial for centrosomal complex concentration of proteins involved in the cell cycle. This points to dysfunctions of BRCA1 in the ubiquitination process in conjunction with subcellular mislocalization of a large portion of BRCA1 protein in neurons during neurodegeneration. This data together suggests that modulation of BRCA1 levels and activity is crucial for different brain conditions. The observation that BRCA1 is essential for embryonic development of the cerebral cortex raises the question of further consequences of BRCA1 activity in mature neurons in various pathological states, especially in neurodegeneration.
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BRCA1 IN CELL DEATH SIGNALING Overexpression of BRCA1 was shown to induce proapoptotic signaling pathways, which sequentially involve H-Ras, MEKK4, JNK, Fas ligand/Fas interactions, and caspase-9 activation, for instance. The action of BRCA1, either protective or prodeath, largely depends on its protein structure and subcellular location. The presence of wild-type BRCA1 promoted the apoptotic response, whereas dominant negative BRCA1 truncation mutants diminished it. Under stress, the efficiency and capacity for DNA repair mediated by the ATM/BRCA1 cell signaling network depends on the expression levels of both B
DOI: 10.1021/acschemneuro.8b00149 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience
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long before other pathologies occur. An increase in BRCA1 levels ultimately results in neuron death.
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AUTHOR INFORMATION
Corresponding Author
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*E-mail:
[email protected].
BRCA1 IN ALZHEIMER’S DISEASE AND OTHER NEURODEGENERATIVE DISORDERS Only few studies have described the role of BRCA1 together with its whole functional network involving DDR and CCC. One of the latest studies demonstrated a hypomethylated region of the BRCA1 promoter, accompanied by an upregulation and cytoplasmic mislocalization of the BRCA1 protein in post-mortem brains from elderly Alzheimer’s disease patients.4 Mano et al.4 found that BRCA1 was mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, leading to DNA fragmentation. Also, BRCA1 dysfunction under the burden of Aβ was consistent with deterioration of genomic integrity and synaptic plasticity, observed in AD brains. Mano et al.4 suggested that loss of DNA integrity is a central contributing factor in AD pathogenesis. Consistently, in our recent work, using primary fibroblasts and neurons from young familial AD patients, we have shown an increased content, activity, and cytosolic relocalization of BRCA1 phosphorylated at Ser1524 upon DDR induction.3 Our further examinations suggested dual mechanisms of action of BRCA1. On the one hand, BRCA1 may affect the subcellular turnover of presenilin 1 (PS1), which was demonstrated by its colocalization with BRCA1 and its increased ubiquitination. Consequently, this may result in abnormal processing of Aβ. On the other hand, BRCA1 could induce pro-apoptotic signaling by activating the Cdc25C protein, known as one of the main mediators of cell cycle re-entry in postmitotic neurons (Figure 1).3 Another study showed a depletion of total nonphosphoBRCA1, which correlated with accumulation of Aβ in the hippocampus in post-mortem brains of sporadic AD patients. Notably, the remaining nondegenerating neurons in AD brains displayed an elevated content of the BRCA1 protein compared to the control neurons.5 In the light of these data, we propose that the observed enhanced expression of active phosphoBRCA1 in neurons could play an important role in cell death signaling in Alzheimer’s disease and its hyperactivation could precede the ultimate neuronal loss and BRCA1 depletion. Furthermore, we propose that BRCA1 upregulation has different implications at different neurodevelopmental stages, playing different roles in neuronal precursors, in mature healthy neurons, and in mature AD neurons. We suggest that the prodromal phase of the disease could start with BRCA1 overactivation, resulting in ultimate BRCA1 depletion in the final stage of the disease, as suggested by Suberbielle et al.5 All above-described studies have significantly enriched the knowledge on the role of BRCA1 in the degenerating brain and paved the way for further research.
ORCID
M. Wezyk: 0000-0001-7498-4610 Funding
The study was supported by the National Science Centre (Poland) Grant “SONATA6”, No. G1119-2013/09/D/NZ3/ 01348. Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Nakanishi, A., Minami, A., Kitagishi, Y., Ogura, Y., and Matsuda, S. (2015) BRCA1 and p53 tumor suppressor molecules in Alzheimer’s disease. Int. J. Mol. Sci. 16, 2879−2892. (2) Pao, G. M., Zhu, Q., Perez-Garcia, C. G., Chou, S. J., Suh, H., Gage, F. H., O’Leary, D. D., and Verma, I. M. (2014) Role of BRCA1 in brain development. Proc. Natl. Acad. Sci. U. S. A. 111, E1240− E1248. (3) Wezyk, M., Szybinska, A., Wojsiat, J., Szczerba, M., Day, K., Ronnholm, H., Kele, M., Berdynski, M., Peplonska, B., Fichna, J. P., Ilkowski, J., Styczynska, M., Barczak, A., Zboch, M., FilipekGliszczynska, A., Bojakowski, K., Skrzypczak, M., Ginalski, K., Kabza, M., Makalowska, I., Barcikowska-Kotowicz, M., Wojda, U., Falk, A., and Zekanowski, C. (2018) Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer’s Disease. J. Alzheimer's Dis. 62, 175. (4) Mano, T., Nagata, K., Nonaka, T., Tarutani, A., Imamura, T., Hashimoto, T., Bannai, T., Koshi-Mano, K., Tsuchida, T., Ohtomo, R., Takahashi-Fujigasaki, J., Yamashita, S., Ohyagi, Y., Yamasaki, R., Tsuji, S., Tamaoka, A., Ikeuchi, T., Saido, T. C., Iwatsubo, T., Ushijima, T., Murayama, S., Hasegawa, M., and Iwata, A. (2017) Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 114, E9645−E9654. (5) Suberbielle, E., Djukic, B., Evans, M., Kim, D. H., Taneja, P., Wang, X., Finucane, M., Knox, J., Ho, K., Devidze, N., Masliah, E., and Mucke, L. (2015) DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nat. Commun. 6, 8897.
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FUTURE PERSPECTIVES It would be interesting to explore in the future both the whole BRCA1-related network and the therapeutic potential of BRCA1 in AD. This would involve testing several already available drugs targeting BRCA1. Knowing that DDR and oxidative stress are generally recognized in neurodegenerative conditions, we should continue our future studies on BRCA1 in various brain pathologies, such as amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). C
DOI: 10.1021/acschemneuro.8b00149 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
