This constitutes a new research line initiated by Dr. Christian Griñán-Ferré, by using C. elegans, as well as several mice models of neurodegeneration. The research interest is the development of new chemical entities based on epigenetics to ameliorate and prevent neurodegenerative diseases, including brain rare disorders. He is also interested in the implications of the transgenerational epigenetic inheritance in the cognitive decline risk for the next generation. The advanced research projects included G9a/GLP inhibitors.
Overview
Epigenetics is emerging as the missing link among genetic inheritance, environmental influences, and body and brain health status. In the brain, specific changes in nucleic acids or their associated proteins in neurons and glial cells might imprint differential patterns of gene activation that will favor either cognitive enhancement or cognitive loss for more than one generation. Furthermore, derangement of age-related epigenetic signaling is appearing as a significant risk factor for illnesses of aging, including neurodegeneration and Alzheimer’s disease (AD). Therefore, better knowledge of epigenetic mechanisms might provide hints and clues in the triggering and progression of AD. Intense research in experimental models suggests that molecular interventions for modulating epigenetic mechanisms might have therapeutic applications to promote cognitive maintenance through an advanced age. Our primary goal is to gain comprehension of how the epigenetic mechanisms modulate the CNS in response to the environment. Thus, in the epigenetic information give rise to deregulation of the expression, resulting in the development of several pathologies, including AD.
Research directions
The role of epigenetics in the control of transcriptional mechanisms comprises one of the earliest emerging fields in senescent processes. These aging-associated transcriptional signatures appear to be controlled by reciprocal regulation among chromatin-modifying enzymes, epigenetic marks, and microRNAs (miRNAs).
Pharmacological Interventions
Histone epigenetic modifications include acetylation, methylation, phosphorylation, and ubiquitination. Growing evidence suggests that histone methyltransferases act as a crucial regulator in human diseases. G9a and G9a-like (GLP) protein are lysine methyltransferases that form a heterodimeric complex able to mono- and di-methylate lysine 9 of histone H3 (H3K9me1 and H3K9me2) of the N-terminal tail. Those epigenetic modifications lead to transcription repression. The G9a/GLP complex plays a role in learning and memory because its inhibition participates in the maintenance of long-term potentiation (LTP), long-term depression (LTD), and also increases Bdnf gene expression, among others.
The research aims to evaluate the beneficial effects of the pharmacological inhibition activity of G9a/GLP with different small-molecules by using the transgenic AD strains of C elegans and two mice models of AD, evaluating epigenetic changes, cognitive improvement, and the influence of the G9a/GLP complex inhibition in amyloid pathology, OS, neuroinflammation, and neuronal plasticity.
