Wanda Haeck

Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis

Oligodendrocytes are well known targets for immune-mediated and infectious diseases, and have been suggested to play a role in neurodegeneration. Here, we report the involvement of oligodendrocytes and their progenitor cells in the ventral grey matter of the spinal cord in amyotrophic lateral sclerosis, a neurodegenerative disease of motor neurons. Degenerative changes in oligodendrocytes were abundantly present in human patients with amyotrophic lateral sclerosis and in an amyotrophic lateral sclerosis mouse model. In the mouse model, morphological changes in grey matter oligodendrocytes became apparent before disease onset, increasingly so during disease progression, and oligodendrocytes ultimately died. This loss was compensated by increased proliferation and differentiation of oligodendrocyte precursor cells. However, these newly differentiated oligodendrocytes were dysfunctional as suggested by their reduced myelin basic protein and monocarboxylate transporter 1 expression. Mutant superoxide dismutase 1 was found to directly affect monocarboxylate transporter 1 protein expression. Our data suggest that oligodendroglial dysfunction may be a contributor to motor neuron degeneration in amyotrophic lateral sclerosis.

Bicyclic-Capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot–Marie–Tooth Disease

Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound 23d that possesses improved biochemical, functional, and druglike properties compared to tubastatin A.

Synthesis and SAR assessment of novel Tubathian analogs in the pursuit of potent and selective HDAC6 inhibitors

The synthesis of novel isoform-selective HDAC inhibitors is considered to be an important, emerging field in medicinal chemistry. In this paper, the preparation and assessment of thirteen selective HDAC6 inhibitors is disclosed, elaborating on a previously developed thiaheterocyclic Tubathian series. All compounds were evaluated in vitro for their ability to inhibit HDAC6, and a selection of five potent compounds was further screened toward all HDAC isoforms (HDAC1-11). The capability of these Tubathian analogs to inhibit α-tubulin deacetylation was assessed as well, and ADME/Tox data were collected. This thorough SAR evaluation revealed that the oxidized, para-substituted hydroxamic acids can be recognized as valuable lead structures in the pursuit of novel potent and selective HDAC6 inhibitors.

Inhibition of histone deacetylase 6 (HDAC6) protects against vincristine-induced peripheral neuropathies and inhibits tumor growth

As cancer is becoming more and more a chronic disease, a large proportion of patients is confronted with devastating side effects of certain anti-cancer drugs. The most common neurological complications are painful peripheral neuropathies. Chemotherapeutics that interfere with microtubules, including plant-derived vinca-alkaloids such as vincristine, can cause these chemotherapy-induced peripheral neuropathies (CIPN). Available treatments focus on symptom alleviation and pain reduction rather than prevention of the neuropathy. The aim of this study was to investigate the potential of specific histone deacetylase 6 (HDAC6) inhibitors as a preventive therapy for CIPN using multiple rodent models for vincristine-induced peripheral neuropathies (VIPN). HDAC6 inhibition increased the levels of acetylated α-tubulin in tissues of rodents undergoing vincristine-based chemotherapy, which correlates to a reduced severity of the neurological symptoms, both at the electrophysiological and the behavioral level. Mechanistically, disturbances in axonal transport of mitochondria is considered as an important contributing factor in the pathophysiology of VIPN. As vincristine interferes with the polymerization of microtubules, we investigated whether disturbances in axonal transport could contribute to VIPN. We observed that increasing α-tubulin acetylation through HDAC6 inhibition restores vincristine-induced defects of axonal transport in cultured dorsal root ganglion neurons. Finally, we assured that HDAC6-inhibition offers neuroprotection without interfering with the anti-cancer efficacy of vincristine using a mouse model for acute lymphoblastic leukemia. Taken together, our results emphasize the therapeutic potential of HDAC6 inhibitors with beneficial effects both on vincristine-induced neurotoxicity, as well as on tumor proliferation.

HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease.

Patients with Charcot-Marie-Tooth disease with predominant axonal loss (CMT2) show extensive genetic heterogeneity. Benoy et al. demonstrate a link between CMT2 and histone deacetylase 6 (HDAC6), which controls the acetylation of α-tubulin, and propose that pharmacological inhibition of HDAC6 has therapeutic potential in CMT2 genetic variants.

Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity

Summary RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity and identified a previously unrecognized synergistic effect between the N-terminal prion-like domain and the C-terminal arginine-rich domain to mediate toxicity. Although the prion-like domain is generally considered to mediate aggregation of FUS, we find that arginine residues in the C-terminal low-complexity domain are also required for maturation of FUS in cellular stress granules. These data highlight an important role for arginine-rich domains in the pathology of RNA-binding proteins.

MYRRHA, A MULTIPURPOSE ACCELERATOR DRIVEN SYSTEM FOR R&D - PRESENT STATUS

One of the SCK.CEN core competencies is and has at all times been the conception, design and realisation of large nuclear research facilities such as BR1, BR2, BR3, VENUS reactors, LHMA hot-cells, or HADES underground research laboratory (URL) for waste disposal. SCK.CEN has then operated these facilities successfully thanks to the high degree of qualification and competency of its personnel and by inserting these facilities in international research networks, contributing hence to the development of crucial aspects of nuclear energy. One of the main SCK.CEN research facility, namely BR2, is nowadays arriving at an age of 40 years just like the major materials testing reactors (MTR) in the world and in Europe (HFR (EU-Petten), OSIRIS (F-Saclay), R2 (Sw-Studsvik)). MYRRHA has been conceived as a potential facility for replacing BR2 and to be a fast spectrum facility complementary to the thermal spectrum RJH (Reacteur Jules Horowitz) facility in France. This situation would give Europe a full research capability in terms of nuclear R&D. Furthermore, the disposal of radioactive wastes resulting from industrial nuclear energy production has still to find a fully satisfactory solution, especially in terms of environmental and social acceptability. As a consequence, most countries with significant nuclear power generating capacity are currently investigating various options for the disposal of their nuclear waste. Scientists are looking for ways to drastically reduce (by a factor of 100 or more) the radio-toxicity of the High Level Waste (HLW) to be stored in a deep geological repository, and to reduce the time needed to reach the radioactivity level of the fuel originally used to produce energy. This can be achieved via the development of the Partitioning and Transmutation and burning MAs and to a less extent LLFPs in Accelerator Driven Systems. The MYRRHA project contribution will be in helping to demonstrate the ADS concept at reasonable power level and the demonstration of the technological feasibility of MA and LLFP transmutation in real conditions.