Biomedical subjects

Edoardo Marcora

Publications and source records attributed to Edoardo Marcora.

3 recordsLinked to original sources

PubMed2025

Lymphoid gene expression supports neuroprotective microglia function.

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)1. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic2. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation3,4. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1low microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1low CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.

Microglia↗

PubMed2005

Context-dependent regulation of NeuroD activity and protein accumulation.

NeuroD/BETA2 (referred to as NeuroD hereafter) is a basic helix-loop-helix (bHLH) transcription factor that is required for the development and survival of a subset of neurons and pancreatic endocrine cells in mice. Gain-of-function analyses demonstrated that NeuroD can (i) convert epidermal fate into neuronal fate when overexpressed in Xenopus embryos, and (ii) activate the insulin promoter in pancreatic beta cell lines in response to glucose stimulation. In glucose-stimulated INS-1 pancreatic beta cells, mutations of S259, S266, and S274 to alanines inhibited the ability of NeuroD to activate the insulin promoter. Phosphorylation of those serine residues by ERK1/2 was required for NeuroD activity in that assay. To determine whether the same residues are implicated in the neurogenic activity of NeuroD, we mutated the conserved S259, S266, and S274 of Xenopus NeuroD to alanines (S259A, S266A, and S274A), and performed an ectopic neurogenesis assay in Xenopus embryos. In contrast to what has been observed in the pancreatic beta cell line, the S266A and S274A mutant forms of Xenopus NeuroD displayed significantly increased abilities to form ectopic neurons, while S259A had little effect. In addition, S266A and S274A of Xenopus NeuroD resulted in increased accumulation of protein in the injected embryos while the corresponding mutations on mouse NeuroD did not have the same effect in an insulinoma cell line. Our results demonstrate that the consequence of NeuroD protein modification is context-dependent at both the molecular and functional levels.

Amino Acid Sequence↗

PubMed2003

Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2.

NeuroD (ND) is a basic helix-loop-helix transcription factor important for neuronal development and survival. By using a yeast two-hybrid screen, we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2), both of which are known to interact with huntingtin (Htt). Htt is a ubiquitous protein important for neuronal transcription, development, and survival, and loss of its function has been implicated in the pathogenesis of Huntington's disease, a neurodegenerative disorder. However, the mechanism by which Htt exerts its neuron-specific function at the molecular level is unknown. Here we report that Htt interacts with ND via HAP1, and that MLK2 phosphorylates and stimulates the activity of ND. Furthermore, we show that Htt and HAP1 facilitate the activation of ND by MLK2. To our knowledge, ND is the first example of a neuron-specific transcription factor involved in neuronal development and survival whose activity is modulated by Htt. We propose that Htt, together with HAP1, may function as a scaffold for the activation of ND by MLK2.

Alkaline Phosphatase↗