Wilhelm Christaller’s research while affiliated with Grenoble Alpes University and other places

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Publications (8)


Figure 1. Corticosteroid Treatment Reduces Cortico-Hippocampal BDNF Transport (A) Schematic of the three-compartment microfluidic device. (B) Cortical axons (Tau positive) cross the axonal channels and contact hippocampal dendrites (MAP2 positive) in the synaptic chamber. Scale bar, 30 mm. (C) Representative kymographs show BDNF vesicles trafficking in WT cortical axons treated or not (with DMSO) for 3 h with dexamethasone (DXM). Graphs correspond to the corresponding kinetic analyses (at least 76 axons analyzed in 4 different cultures). Scale bar, 10 mm. (D and E) Cortical neurons were treated (D) or transduced with viruses (E), as indicated, and extracts were analyzed by immunoblotting for the presence of the phosphorylated forms of HTT at CDK5 sites (P-S1181 and P-S1201), HTT (D7F7), p35, and p25. Rosco, roscovitine. Histograms correspond to the quantitative evaluation of the indicated proteins (at least 5 independent cultures). Error bars, SEM. *p < 0.05, **p < 0.01. See also Figure S1.
Figure 3. Huntingtin Is Phosphorylated at CDK5 Sites upon Chronic CORT Treatment (A) WT mice were treated with CORT or vehicle for 4 to 6 weeks in their drinking water. (B) Whole cortical and hippocampal (Hipp.) extracts were analyzed by immunoblotting for the presence of the phosphorylated forms of HTT at CDK5 sites (P-S1181 and P-S1201), total HTT (D7F7), CDK5, p35, p25, and a-tubulin. (C) Histograms correspond to the quantitative evaluation of the indicated proteins (at least 4 animals). (D and E) Whole cortical and hippocampal extracts were analyzed by immunoblotting for the presence of proBDNF, mature BDNF, and a-tubulin. Histograms correspond to the quantitative evaluation of the indicated proteins (at least 4 animals). Error bars, SEM. *p < 0.05, **p < 0.01, ****p < 0.0001.
Figure 4. Phosphorylation of HTT at S1181/S1201 Influences Hippocampal Neurogenesis (A-C) Cells counts were performed in the DG of vehicle-and CORT-treated WT and Hdh S1181A/S1201A mice (at least 4 for animals per condition) to quantify proliferation (Ki67+ cells, A), survival (BrdU+ cells, B), and immature neurons (DCX+ cells, C). *p < 0.05, **p < 0.01, ***p < 0.001. (D) Representative images show BrdU+ surviving cells (cyan) expressing (or not) the terminal marker for granule cell differentiation calbindin (magenta) on DG sections of WT and Hdh S1181A/S1201A mice treated with vehicle or CORT. (E) The histogram shows the quantification of the number of BrdU+ and calbindin+ cells (3 animals per condition). *p <0.05, **p < 0.01. (F and G) Dendritic length (F) and complexity (G) were evaluated in both genotypes and treatment conditions (3 animals per condition). (H) Representative drawings of dendrites of DCX-positive neurons. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 comparing the Hdh S1181A/S1201A vehicle group with the WT vehicle group, $ p < 0.05, $$ p < 0.01, $$$ p < 0.001, $$$$ p < 0.0001 comparing the Hdh S1181A/S1201A -CORT group with the WT CORT group. Error bars, SEM. See also Figure S2.
Chronic Corticosterone Elevation Suppresses Adult Hippocampal Neurogenesis by Hyperphosphorylating Huntingtin
  • Article
  • Full-text available

July 2020

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113 Reads

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29 Citations

Cell Reports

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Wilhelm Christaller

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Chronic exposure to stress is a major risk factor for neuropsychiatric disease, and elevated plasma corticosterone (CORT) correlates with reduced levels of both brain-derived neurotrophic factor (BDNF) and hippocampal neurogenesis. Precisely how these phenomena are linked, however, remains unclear. Using a cortico-hippocampal network-on-a-chip, we find that the glucocorticoid receptor agonist dexamethasone (DXM) stimulates the cyclin-dependent kinase 5 (CDK5) to phosphorylate huntingtin (HTT) at serines 1181 and 1201 (S1181/1201), which retards BDNF vesicular transport in cortical axons. Parallel studies in mice show that CORT induces phosphorylation of these same residues, reduces BDNF levels, and suppresses neurogenesis. The adverse effects of CORT are reduced in mice bearing an unphosphorylatable mutant HTT (HdhS1181A/S1201A). The protective effect of unphosphorylatable HTT, however, disappears if neurogenesis is blocked. The CDK5-HTT pathway, which regulates BDNF transport in the cortico-hippocampal network, thus provides a missing link between elevated CORT levels and suppressed neurogenesis.

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CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington's disease

July 2019

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620 Reads

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83 Citations

Brain

Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The main pathway for brain cholesterol elimination is its hydroxylation into 24S-hydroxycholesterol by the cholesterol 24-hydrolase, CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the pathogenesis and progression of neurodegenerative disorders, and that increasing its levels in the brain is neuroprotective. However, the mechanisms underlying this neuroprotection remain to be fully understood. Huntington's disease is a fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG expansion in huntingtin's gene. Among the multiple cellular and molecular dysfunctions caused by this mutation, altered brain cholesterol homeostasis has been described in patients and animal models as a critical event in Huntington's disease. Here, we demonstrate that a gene therapy approach based on the delivery of CYP46A1, the rate-limiting enzyme for cholesterol degradation in the brain, has a long-lasting neuroprotective effect in Huntington's disease and counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 Huntington's disease knock-in mice, CYP46A1 prevented neuronal dysfunctions and restored cholesterol homeostasis. These events were associated to a specific striatal transcriptomic signature that compensates for multiple mHTT-induced dysfunctions. We thus explored the mechanisms for these compensations and showed an improvement of synaptic activity and connectivity along with the stimulation of the proteasome and autophagy machineries, which participate to the clearance of mutant huntingtin (mHTT) aggregates. Furthermore, BDNF vesicle axonal transport and TrkB endosome trafficking were restored in a cellular model of Huntington's disease. These results highlight the large-scale beneficial effect of restoring cholesterol homeostasis in neurodegenerative diseases and give new opportunities for developing innovative disease-modifying strategies in Huntington's disease.


Neuronal network maturation differently affects secretory vesicles and mitochondria transport in axons

September 2018

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296 Reads

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66 Citations

Abstract Studying intracellular dynamics in neurons is crucial to better understand how brain circuits communicate and adapt to environmental changes. In neurons, axonal secretory vesicles underlie various functions from growth during development to plasticity in the mature brain. Similarly, transport of mitochondria, the power plant of the cell, regulates both axonal development and synaptic homeostasis. However, because of their submicrometric size and rapid velocities, studying the kinetics of these organelles in projecting axons in vivo is technically challenging. In parallel, primary neuronal cultures are adapted to study axonal transport but they lack the physiological organization of neuronal networks, which in turn may bias observations. We previously developed a microfluidic platform to reconstruct a physiologically-relevant and functional corticostriatal network in vitro that is compatible with high-resolution videorecording of axonal trafficking. Here, using this system we report progressive changes in axonal transport kinetics of both dense core vesicles and mitochondria that correlate with network development and maturation. Interestingly, axonal flow of both types of organelles change in opposite directions, with rates increasing for vesicles and decreasing for mitochondria. Overall, our observations highlight the need for a better spatiotemporal control for the study of intracellular dynamics in order to avoid misinterpretations and improve reproducibility.





Reconstituting Corticostriatal Network on-a-Chip Reveals the Contribution of the Presynaptic Compartment to Huntington’s Disease

January 2018

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336 Reads

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186 Citations

Cell Reports

Huntington's disease (HD), a devastating neurodegenerative disorder, strongly affects the corticostriatal network, but the contribution of pre- and postsynaptic neurons in the first phases of disease is unclear due to difficulties performing early subcellular investigations in vivo. Here, we have developed an on-a-chip approach to reconstitute an HD corticostriatal network in vitro, using microfluidic devices compatible with subcellular resolution. We observed major defects in the different compartments of the corticostriatal circuit, from presynaptic dynamics to synaptic structure and transmission and to postsynaptic traffic and signaling, that correlate with altered global synchrony of the network. Importantly, the genetic status of the presynaptic compartment was necessary and sufficient to alter or restore the circuit. This highlights an important weight for the presynaptic compartment in HD that has to be considered for future therapies. This disease-on-a-chip microfluidic platform is thus a physiologically relevant in vitro system for investigating pathogenic mechanisms and for identifying drugs.


B41 HD on chip : reconstituting the cortico-striatal network on microfluidics to study intracellular trafficking and synaptic transmission

September 2016

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29 Reads

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3 Citations

Journal of Neurology, Neurosurgery, and Psychiatry

Most of the cellular or molecular studies in HD used so far separated cultures of striatal or cortical neurons. However, in the brain these neurons are connected and form a particular network that is defective in HD. The polarised nature of neurons and the size and density of synapses complicates the manipulation and visualisation of specific events taking place in axons or dendrites and of specific synaptic transmission within the cortico-striatal network. To overcome these limitations, we developed several microfluidic systems compatible with high-resolution videomicroscopy and connected to microelectrode arrays (MEA) to reconstitute and identify each component of the corticostriatal network. The microfluidic system directs the formation of identified synapses separately between cortical axons and striatal dendrites and soma. In parallel, a multielectrode substrate monitors and controls presynaptic and postsynaptic activity independently. Using this multicomplex system we are investigating how the trafficking of synaptic vesicles or mitochondria along axons is regulated by presynaptic and postsynaptic patterns in the corticostriatal network in health and HD. In addition, the system allows modifying the genetic status of the cortical or striatal neurons as a way to selectively investigate how disease neurons differentially affect pre or post-synaptic events in HD and overall alter synapse function.

Citations (5)


... Similarly, chronic CORT administration was shown to suppress AHN via decreased BDNF vesicular transport from hungtington hyperphosphorylation by CDK5. Conversely, an unphosphorylatable form of huntington protects against the depressive effects of CORT on AHN (26). Past studies show that glucocorticoid receptors (GRs) interact with TrkB for BDNF, that chronic CORT treatment decreased TrkB-GR interaction and suppressed BDNF-mediated glutamate release via suppression of BD-NF-activated PLC-γ (phospholipase C-γ)/ Ca 2+ signaling pathways (27). ...

Reference:

Corticosterone-Mediated BDNF Changes and Their Effects on Adult Neurogenesis in Depression
Chronic Corticosterone Elevation Suppresses Adult Hippocampal Neurogenesis by Hyperphosphorylating Huntingtin

Cell Reports

... More recently, an intranasal delivery approach has shown great potential in mouse models of HD. 2 A trial to restore cholesterol biosynthesis in HD patients with AB-1001 gene therapy has started but paused until 2025. 4 Formerly known as hCYP46A1, this gene converts approximately 6 mg of brain cholesterol per day into its hydrophilic catabolite, 24-hydroxycholesterol (24OHC), which then leaves the brain and is detectable in plasma. This therapy has been primarily designed for Alzheimer's disease (AD), where cholesterol accumulates pathologically and contributes to aggregate formation, while in HD the reverse situation is seen. ...

CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington's disease

Brain

... 4−6 Additionally, CCCs are employed to investigate axonal degeneration and regeneration, 7,8 as well as the transport of proteins, ion channels, and organelles along axons. 9,10 Furthermore, CCCs can be utilized to evaluate functional aspects such as neuronal excitability and cellular communication between distinct neuronal populations or between neurons and non-neuronal cells 11,12 (for extensive reviews on CCC applications in NDs, see refs 3,13−15). ...

Neuronal network maturation differently affects secretory vesicles and mitochondria transport in axons

... The microfluidic device was developed by the Institut de Neurophysiophatologie (Timone, Marseille, France). It was fabricated using soft lithography as previously described [25,26]. First, a master mold of the chamber and microchannel was fabricated in polymerized resin (type R123, Soloplast, Vosschemie, France). ...

Reconstituting Corticostriatal Network on-a-Chip Reveals the Contribution of the Presynaptic Compartment to Huntington’s Disease

Cell Reports

... Among them, PDMS-based microfluidic circuits have emerged as highly versatile tools providing many suitable properties for positioning, culturing and interfacing large populations of neurons 12,13 . Since the first demonstrations, PDMS-based microfluidics has been used for modeling brain circuits on a chip [14][15][16][17] , as well as for single-neuron analysis [18][19][20][21][22] . This approach combines neuron-adhesive coating and physical barriers for efficient cell adhesion and time-stable architectures 13,23-26 while maintaining high optical transparency for high-resolution imaging 27,28 . ...

B41 HD on chip : reconstituting the cortico-striatal network on microfluidics to study intracellular trafficking and synaptic transmission
  • Citing Article
  • September 2016

Journal of Neurology, Neurosurgery, and Psychiatry