Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients

Robicsek, Odile; Karry, Rachel; Petit, Isabelle; Salman-Kesner, N; Müller, Franz‐Josef; Klein, Ehud; Aberdam, Daniel; Ben‐Shachar, Dorit

doi:10.1038/mp.2013.67

Cited by 207 publications

(190 citation statements)

References 62 publications

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“…We have previously reported that a significant fraction of the gene signature of schizophrenia hiPSC-derived neurons is conserved in schizophrenia hiPSC-derived neural progenitor cells (NPCs), indicating that NPCs may be a useful cell type for studying the molecular pathways contributing to schizophrenia 1 . We and others have reported aberrant migration, increased oxidative stress and reactive oxygen species, sensitivity to sub-threshold environmental stresses and impaired mitochondrial function in schizophrenia hiPSC NPCs 1,[4][5][6] , as well as decreased neuronal connectivity and synaptic function in schizophrenia hiPSC neurons 5,[7][8][9][10] . If the molecular factors contributing to aberrant migration and/or oxidative stress in schizophrenia hiPSC NPCs also underlie the reduced neuronal connectivity in schizophrenia hiPSC-derived neurons, NPCs could be a robust and highly replicative neural population with which to study the mechanisms responsible for disease.…”

Section: Introductionmentioning

confidence: 99%

A Guide to Generating and Using hiPSC Derived NPCs for the Study of Neurological Diseases

Topol

Tran

Brennand

2015

JoVE

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Post-mortem studies of neurological diseases are not ideal for identifying the underlying causes of disease initiation, as many diseases include a long period of disease progression prior to the onset of symptoms. Because fibroblasts from patients and healthy controls can be efficiently reprogrammed into human induced pluripotent stem cells (hiPSCs), and subsequently differentiated into neural progenitor cells (NPCs) and neurons for the study of these diseases, it is now possible to recapitulate the developmental events that occurred prior to symptom onset in patients. We present a method by which to efficiently differentiate hiPSCs into NPCs, which in addition to being capable of further differentiation into functional neurons, can also be robustly passaged, freeze-thawed or transitioned to grow as neurospheres, enabling rapid genetic screening to identify the molecular factors that impact cellular phenotypes including replication, migration, oxidative stress and/or apoptosis. Patient derived hiPSC NPCs are a unique platform, ideally suited for the empirical testing of the cellular or molecular consequences of manipulating gene expression. Video LinkThe video component of this article can be found at

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Section: Introductionmentioning

confidence: 99%

A Guide to Generating and Using hiPSC Derived NPCs for the Study of Neurological Diseases

Topol

Tran

Brennand

2015

JoVE

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“…In accordance, a reduction in voltage-activated sodium and potassium currents, which may be linked to deregulated calcium homeostasis, has been observed in ALS iPSC-derived motor neurons [107]. from patients with schizophrenia and demonstrated that dopaminergic neurons failed to differentiate, whereas glutamatergic cells were not able to fully mature [110]. Impaired mitochondrial respiration was observed in both neuronal types as well as dissipation of mitochondrial membrane potential and disturbances in mitochondrial network structure.…”

Section: Mitochondrial Impairment In Ipsc Models Of Brain Disordersmentioning

confidence: 56%

Energy metabolism in neuronal/glial induction and in iPSC models of brain disorders

Mlody

Lorenz

Inak

et al. 2016

Seminars in Cell & Developmental Biology

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The metabolic switch associated with the reprogramming of somatic cells to pluripotency has received increasing attention in recent years. However, the impact of mitochondrial and metabolic modulation on stem cell differentiation into neuronal/glial cells and related brain disease modeling still remains to be fully addressed. Here, we seek to focus on this aspect by first addressing brain energy metabolism and its inter-cellular metabolic compartmentalization. We then review the findings related to the mitochondrial and metabolic reconfiguration occurring upon neuronal/glial specification from pluripotent stem cells (PSCs). Finally, we provide an update of the PSC-based models of mitochondria-related brain disorders and discuss the challenges and opportunities that may exist on the road to develop a new era of brain disease modeling and therapy.3 Mitochondrial remodeling in cell fate specificationThe majority of cellular energy in form of ATP is provided through oxidative phosphorylation (OXPHOS) by mitochondria. Mitochondria are also involved in the metabolism of amino acids, fatty acids, and steroids, and contribute to cell signaling through the modulation of reactive oxygen species (ROS), calcium homeostasis, and apoptosis [1].Furthermore, intermediate metabolites can cross-talk to the nucleus acting as epigenetic regulators [2].In low oxygen environments, a typical conversion process of 1 molecule of glucose results into 2 molecules of ATP through glycolysis in the cytosol, which terminates with the secretion of lactate into the extracellular environment. Under normoxic conditions, the 2 molecules of pyruvate, generated through glycolysis, can enter the mitochondria and undergo further oxidation in the tricarboxylic acid (TCA) cycle, leading to the production of additional 34 molecules of ATP [3]. However, under conditions requiring high proliferative rates, this mitochondrial-based energy generation may be shut-down despite the presence of normal oxygen concentration [4]. This situation, known as aerobic glycolysis or Warburg effect, was first described by Otto Warburg in the context of cancer [5]. Recent studies demonstrated that a Warburg-like effect may also represent a defining feature of stem cells [6][7][8].Since distinct cell types have different energy demands, regulation of mitochondria may represent an essential process allowing the cells to meet their biological requirements.The metabolic identity of cells may in fact be influenced not only by changes in the expression of metabolic genes, but also by modulation of mitochondrial dynamics and mitochondrial DNA (mtDNA) copy number [9,10]. In particular, energy metabolism is shifted towards glycolysis in stem cells, whose mitochondria appear round-shaped with poorlydeveloped cristae [11,12]. This is in sharp contrast to cells with high energy demands, like muscle cells and neurons, where mitochondria are abundant in number and exhibit tubularlike morphology and cristae-rich structures [13]. 4As a consequence, acquisition of a distinct metabot...

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“…However, accumulating evidence suggests mitochondria as an additional pathological factor in schizophrenia. Mitochondrial dysfunction and a disturbance in energy metabolism have been observed in schizophrenia patients and, likewise, mitochondrial disorders may present with psychotic, affective and cognitive symptoms (Manji et al, 2012;Robicsek et al, 2013). Recent data revealed that nuclear genes encoding mitochondrially localised proteins are over-represented among large, rare copy-number variations in schizophrenia patients, lending credence to the mitochondrial dysfunction hypothesis (Szatkiewicz et al, 2014).…”

Section: Do Neurons Have a Mechanism To Sense Upcoming Energy Needs?mentioning

confidence: 98%

Mitochondrial biogenesis is required for axonal growth

et al. 2016

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During early development, neurons undergo complex morphological rearrangements to assemble into neuronal circuits and propagate signals. Rapid growth requires a large quantity of building materials, efficient intracellular transport and also a considerable amount of energy. To produce this energy, the neuron should first generate new mitochondria because the pre-existing mitochondria are unlikely to provide a sufficient acceleration in ATP production. Here, we demonstrate that mitochondrial biogenesis and ATP production are required for axonal growth and neuronal development in cultured rat cortical neurons. We also demonstrate that growth signals activating the CaMKKβ, LKB1-STRAD or TAK1 pathways also co-activate the AMPK-PGC-1α-NRF1 axis leading to the generation of new mitochondria to ensure energy for upcoming growth. In conclusion, our results suggest that neurons are capable of signalling for upcoming energy requirements. Earlier activation of mitochondrial biogenesis through these pathways will accelerate the generation of new mitochondria, thereby ensuring energy-producing capability for when other factors for axonal growth are synthesized.

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Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients

Cited by 207 publications

References 62 publications

A Guide to Generating and Using hiPSC Derived NPCs for the Study of Neurological Diseases

A Guide to Generating and Using hiPSC Derived NPCs for the Study of Neurological Diseases

Energy metabolism in neuronal/glial induction and in iPSC models of brain disorders

Mitochondrial biogenesis is required for axonal growth

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