RESUMO
Mitochondria are organelles with recognized key roles in cellular homeostasis, including bioenergetics, redox, calcium signaling, and cell death. Mitochondria are essential for neuronal function, given the high energy demands of the human brain. Consequently, mitochondrial diseases affecting oxidative phosphorylation (OXPHOS) commonly exhibit neurological impairment. Emerging evidence suggests that mitochondria are important not only for mature postmitotic neurons but also for the regulation of neural progenitor cells (NPCs) during the process of neurogenesis. These recent findings put mitochondria as central regulator of cell fate decisions during brain development. OXPHOS mutations may disrupt the function of NPCs and thereby impair the metabolic programming required for neural fate commitment. Promoting the mitochondrial function of NPCs could therefore represent a novel interventional approach against incurable mitochondrial diseases.
Assuntos
Doenças Mitocondriais , Células-Tronco Neurais , Humanos , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Fosforilação OxidativaRESUMO
Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) protein expressed in specific types of glial cells in the nervous system. The expression of GFAP is highly regulated during brain development and in neurological diseases. The presence of distinct GFAP-isoforms in various cell types, developmental stages, and diseases indicates that GFAP (post-)transcriptional regulation has a role in glial cell physiology and pathology. GFAP-isoforms differ in sub-cellular localisation, IF-network assembly properties, and IF-dynamics which results in distinct molecular interactions and mechanical properties of the IF-network. Therefore, GFAP (post-)transcriptional regulation is likely a mechanism by which radial glia, astrocytes, and glioma cells can modulate cellular function.
Assuntos
Astrócitos , Filamentos Intermediários , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Filamentos Intermediários/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Isoformas de Proteínas/genética , Regulação da Expressão GênicaRESUMO
Expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT) causes the neurodegenerative disorder Huntington's disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered male induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. The introduction of a 70Q mutation caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics that was reverted upon overexpression of CHCHD2. Removing the poly-Q tract from HTT normalized CHCHD2 levels and corrected key mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early interventional target for HD.
Assuntos
Encéfalo , Proteínas de Ligação a DNA , Proteína Huntingtina , Doença de Huntington , Células-Tronco Pluripotentes Induzidas , Mitocôndrias , Proteínas Mitocondriais , Organoides , Fatores de Transcrição , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Organoides/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Encéfalo/metabolismo , Encéfalo/patologia , Doença de Huntington/metabolismo , Doença de Huntington/genética , Doença de Huntington/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Mitocôndrias/metabolismo , Mutação , Dinâmica Mitocondrial/genéticaRESUMO
Astrocytes are specialized glial cells that tile the central nervous system (CNS) and perform numerous essential functions. Astrocytes react to various forms of CNS insults by altering their morphology and molecular profile, through a process known as reactive astrogliosis. Accordingly, astrocyte reactivity is apparent in many neurodegenerative diseases, among which one is Alzheimer's disease (AD). Recent clinical trials on early-stage AD have demonstrated that Fortasyn Connect (FC), a multi-nutrient combination providing specific precursors and cofactors for phospholipid synthesis, helps to maintain neuronal functional connectivity and cognitive performance of patients. Several studies have shown that FC may act through its effects on neuronal survival and synaptogenesis, leading to reduced astrocyte reactivity, but whether FC can directly counteract astrocyte reactivity remains to be elucidated. Hence, we developed an in vitro model of reactive astrogliosis using the pro-inflammatory cytokines TNF-α and IFN-γ together with an automated high-throughput assay (AstroScan) to quantify molecular and morphological changes that accompany reactive astrogliosis. Next, we showed that FC is potent in preventing cytokine-induced reactive astrogliosis, a finding that might be of high relevance to understand the beneficial effects of FC-based interventions in the context of neurodegenerative diseases.