The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Againstα-Synuclein-Induced Toxicity

Trabajo presentado en el VII Spanish Worm Meeting (SWN), celebrado en Castelldefels (Barcelona) el 28 y 29 de marzo de 2019.Peer reviewe

Essential role of hypodermal PMP-4 in regulating axon morphology and locomotion in a Caenorhabditis elegans modelo of X-ALD

Trabajo presentado en la V Spanish Worm Meeting, celebrada en Salamanca el 5 y 6 de marzo de 2015.Peer Reviewe

Caenorhabditis elegans RAC1/ced-10 mutants as a new animal model to study very early stages of Parkinson's disease

Altres ajuts: acords transformatius de la UABPatients with Parkinson's disease (PD) display non-motor symptoms arising prior to the appearance of motor signs and before a clear diagnosis. Motor and non-motor symptoms correlate with progressive deposition of the protein alpha-synuclein (Asyn) both within and outside of the central nervous system, and its accumulation parallels neurodegeneration. The genome of Caenorhabditis elegans does not encode a homolog of Asyn, thus rendering this nematode an invaluable system with which to investigate PD-related mechanisms in the absence of interference from endogenous Asyn aggregation. CED-10 is the nematode homolog of human RAC1, a small GTPase needed to maintain the function and survival of dopaminergic neurons against human Asyn-induced toxicity in C. elegans. Here, we introduce C. elegans RAC1/ced-10 mutants as a predictive tool to investigate early PD symptoms before neurodegeneration occurs. Deep phenotyping of these animals reveals that, early in development, they displayed altered defecation cycles, GABAergic abnormalities and an increased oxidation index. Moreover, they exhibited altered lipid metabolism evidenced by the accumulation of lipid droplets. Lipidomic fingerprinting indicates that phosphatidylcholine and sphingomyelin, but not phosphatidylethanolamine or phosphatidylserine, were elevated in RAC1/ced-10 mutant nematodes. These collective characteristics reflect the non-motor dysfunction, GABAergic neurotransmission defects, upregulation of stress response mechanisms, and metabolic changes associated with early-onset PD. Thus, we put forward an easy-to-manipulate preclinical animal model to deepen our understanding of early-stage PD and accelerate the translational path for therapeutic target discovery

The peroxisomal fatty acid transporter ABCD1/PMP-4 is required in the C. elegans hypodermis for axonal maintenance: A worm model for adrenoleukodystrophy

Adrenoleukodystrophy is a neurometabolic disorder caused by a defective peroxisomal ABCD1 transporter of very long-chain fatty acids (VLCFAs). Its pathogenesis is incompletely understood. Here we characterize a nematode model of X-ALD with loss of the pmp-4 gene, the worm orthologue of ABCD1. These mutants recapitulate the hallmarks of X-ALD: i) VLCFAs accumulation and impaired mitochondrial redox homeostasis and ii) axonal damage coupled to locomotor dysfunction. Furthermore, we identify a novel role for PMP-4 in modulating lipid droplet dynamics. Importantly, we show that the mitochondria targeted antioxidant MitoQ normalizes lipid droplets size, and prevents axonal degeneration and locomotor disability, highlighting its therapeutic potential. Moreover, PMP-4 acting solely in the hypodermis rescues axonal and locomotion abnormalities, suggesting a myelin-like role for the hypodermis in providing essential peroxisomal functions for the nematode nervous system.We thank CERCA Program/Generalitat de Catalunya for institutional support. This work was supported by grants from the Autonomous Government of Catalonia [2017SGR1206] to A.P., The Spanish Ministry of Science and Competitivity grants (PC0009/003 and PI1100968 to E. D). This study has been funded by Instituto de Salud Carlos III through the grants [Miguel Servet program CPII16/00016] to S.F. (Co-funded by European Social Fund. ESF investing in your future), and the Center for Biomedical Research on Rare Diseases (CIBERER) to A.P and M.R. S.G. was a fellow of the Autonomous Government of Catalonia [2014FI_B2 00028]. A.C. and J.P. were fellows of IDIBELL

Combined Experimental and Theoretical Investigation of Ligand and Anion Controlled Complex Formation with Unprecedented Structural Features and Photoluminescence Properties of Zinc(II) Complexes

By using two potential tridentate ligands, HL¹ [4-chloro-2-[(2-morpholin-4-yl-ethylimino)-methyl]-phenol] and HL² [4-chloro-2-[(3-morpholin-4-yl-propylimino)-methyl]-phenol], which differ by one methylene group in the alkyl chain, four new Zn^II complexes, namely, [Zn(L²H)₂](ClO₄)₂ (1), [Zn(L¹)(H₂O)₂][Zn(L¹)(SCN)₂] (2), [Zn(L¹)(dca)]n (3), and [Zn₂(L¹)₂(N₃)₂(H₂O)₂] (4) [where dca = dicyanamide anion] were synthesized and structurally characterized. The results indicate that the slight structural difference between the ligands, HL¹ and HL², because of the one methylene group connecting the nitrogen atoms provokes a chemical behavior completely different from what was expected. Any attempt to isolate the Zn(L²) complexes with thiocyanato, dicyanamido, and azide was unsuccessful, and perchlorate complex 1 was always obtained. In contrast, with HL¹ we obtained structural diversity on varying the anions, but we failed to isolate the analogous perchlorate complex of HL¹. Single-crystal X-ray analyses revealed that the morpholine nitrogen of ligand L² is protonated and thus does not take part in coordination with Zn^II in complex 1. On the other hand, the morpholine nitrogen of L¹ is coordinated to Zn^II in 2–4. Of these, 2 and 4 are rare examples of a cocrystallized cationic/anionic complex and of a dinuclear complex bridged by a single azide, respectively. Some of these unexpected findings and some interesting noncovalent interactions leading to the formation of dimeric entities in solid-state compound 4 were rationalized by a DFT approach. Photoluminescence properties of the complexes as well as the ligands were investigated in solution at ambient temperature and at 77 K. The very fast photoinduced electron transfer (PET) from the nitrogen lone pair to the conjugated phenolic moiety is responsible for very low quantum yield (Φ) exhibited by the ligands, whereas complexation prevents PET, thus enhancing the Φ in the complexes. The origin of the electronic and photoluminescence properties of the ligands and complexes was assessed in light of theoretical calculations