The Regulation of MiTF/TFE Transcription Factors Across Model Organisms: from Brain Physiology to Implication for Neurodegeneration

Abstract

The microphthalmia/transcription factor E (MiTF/TFE) transcription factors are responsible for the regulation of various key processes for the maintenance of brain function, including autophagy-lysosomal pathway, lipid catabolism, and mitochondrial homeostasis. Among them, autophagy is one of the most relevant pathways in this frame; it is evolutionary conserved and crucial for cellular homeostasis. The dysregulation of MiTF/TFE proteins was shown to be involved in the development and progression of neurodegenerative diseases. Thus, the characterization of their function is key in the understanding of the etiology of these diseases, with the potential to develop novel therapeutics targeted to MiTF/TFE proteins and to the autophagic process. The fact that these proteins are evolutionary conserved suggests that their function and dysfunction can be investigated in model organisms with a simpler nervous system than the mammalian one. Building not only on studies in mammalian models but also in complementary model organisms, in this review we discuss (1) the mechanistic regulation of MiTF/TFE transcription factors; (2) their roles in different regions of the central nervous system, in different cell types, and their involvement in the development of neurodegenerative diseases, including lysosomal storage disorders; (3) the overlap and the compensation that occur among the different members of the family; (4) the importance of the evolutionary conservation of these protein and the process they regulate, which allows their study in different model organisms; and (5) their possible role as therapeutic targets in neurodegeneration.

Plasticity of Human Microglia and Brain Perivascular Macrophages in Aging and Alzheimer’s Disease

“…Through our GRN analysis, we prioritize MITF as the master regulator of AD risk signatures, governing the expression of numerous AD-associated genes, including APOE, DPYD, TREM2, and PTPRG 13,33,34 . The MITF network is specifically enriched for phagocytic activity markers and has previously been studied as a key regulator of homeostatic microglia functions, in particular for driving autophagic states, and for allowing microglia to move, sense, and clear Aβ/Tau proteinopathies 22,23,[35][36][37] . Moreover, through our CCI analysis, we prioritize ligand-receptor interactions mediating the aggravation of AD progression and place ADAM as key players.…”