Many fundamental cellular processes are affected by epigenetic modulation, and in recent years it has become evident that chromatin-based epigenetic mechanisms underlie important aspects of the aging process. However, despite the fact that age is a prominent risk factor in neurodegenerative disease (ND), there is remarkably little information on the role of epigenetic alterations in mechanisms of ND such as Alzheimer's disease (AD), Parkinson's dementia (PD), frontotemporal degeneration (FTLD) or amyotrophic lateral sclerosis (ALS). We believe that a detailed biological, mechanistic and molecular understanding of the epigenetic factors that are altered in human ND holds promise for an improved understanding of disease pathogenesis and for the development of novel therapeutic interventions. The goals of this Project are to: (1) investigate whether major epigenetic modifications (histone post-translational modifications) change in the context of different NDs using an extensive bank of human samples available from the Penn Center for Neurodegenerative Disease Research (CNDR), (2) use our model systems to discover new epigenetic modifications that underlie ND disease, and (3) test the relevance of novel changes seen in human ND using models of ND. The proposed studies of this multiple-PI and co-Investigator effort will leverage complementary and intersecting interests from our laboratories concerning epigenetics and aging (Berger, Bonini, Johnson), ND (Bonini, Torres and Trojanowski), and the generation and bioinformatic analysis of genome-wide data obtained by chromatin immunoprecipitation followed by second generation sequencing (Gregory, Wang, Berger). The application of our combined expertise to the analysis of the rich collection of CNDR ND brain samples will launch a major new effort in the field of epigenetics in ND. In the broader scientific and medical communities, this effort will promote discoveries of epigenetic mechanisms of ND to provide the foundation for new insights and novel clinical approaches to treat ND.
Advancing age is a major risk factor for neurodegenerative diseases like Alzheimer's disease and Parkinson's dementia, diseases that exact enormous personal suffering and costs to society, yet little is known about precisely how aging contributes to these diseases. Recently it has become evident that changes in the structure called 'chromatin', which organizes our genes and regulates their activity, underlie key aspects of the aging process. We will investigate the precise nature of chromatin changes in brains from people with neurodegenerative diseases, and test how these changes interfere with normal function, thus providing a basis for new classes of diagnostics and therapies that will improve human well-being.
| Nativio, Raffaella; Donahue, Greg; Berson, Amit et al. (2018) Publisher Correction: Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease. Nat Neurosci 21:1018 |
| Cohen, Justin; D'Agostino, Luca; Tuzer, Ferit et al. (2018) HIV antiretroviral therapy drugs induce premature senescence and altered physiology in HUVECs. Mech Ageing Dev 175:74-82 |
| Kennerdell, Jason R; Liu, Nan; Bonini, Nancy M (2018) MiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging. Nat Commun 9:4188 |
| Nativio, Raffaella; Donahue, Greg; Berson, Amit et al. (2018) Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease. Nat Neurosci 21:497-505 |
| Lawrence, Ibiyonu; Bene, Michael; Nacarelli, Timothy et al. (2018) Correlations between age, functional status, and the senescence-associated proteins HMGB2 and p16INK4a. Geroscience 40:193-199 |
| Berson, Amit; Nativio, Raffaella; Berger, Shelley L et al. (2018) Epigenetic Regulation in Neurodegenerative Diseases. Trends Neurosci 41:587-598 |
| Berson, Amit; Sartoris, Ashley; Nativio, Raffaella et al. (2017) TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling. Curr Biol 27:3579-3590.e6 |
| Bonini, Nancy M; Berger, Shelley L (2017) The Sustained Impact of Model Organisms-in Genetics and Epigenetics. Genetics 205:1-4 |
| Bonini, Nancy M; Lee, Edward B; Wasco, Wilma et al. (2017) Editorial overview: Molecular & genetic basis of disease. Curr Opin Genet Dev 44:iv-vi |
| Cohen, Justin; Torres, Claudio (2017) HIV-associated cellular senescence: A contributor to accelerated aging. Ageing Res Rev 36:117-124 |
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