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Glutaric Acid Affects Pericyte Contractility and Migration: Possible Implications for GA-I Pathogenesis

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Abstract

Glutaric acidemia I (GA-I) is an inherited neurometabolic childhood disease characterized by bilateral striatal neurodegeneration upon brain accumulation of millimolar concentrations of glutaric acid (GA) and related metabolites. Vascular dysfunction, including abnormal cerebral blood flow and blood-brain barrier damage, is an early pathological feature in GA-I, although the affected cellular targets and underlying mechanisms remain unknown. In the present study, we have assessed the effects of GA on capillary pericyte contractility in cerebral cortical slices and pericyte cultures, as well as on the survival, proliferation, and migration of cultured pericytes. GA induced a significant reduction in capillary diameter at distances up to ~ 10 μm from the center of pericyte somata. However, GA did not affect the contractility of cultured pericytes, suggesting that the response elicited in slices may involve GA evoking pericyte contraction by acting on other cellular components of the neurovascular unit. Moreover, GA indirectly inhibited migration of cultured pericytes, an effect that was dependent on soluble glial factors since it was observed upon application of conditioned media from GA-treated astrocytes (CM-GA), but not upon direct GA addition to the medium. Remarkably, CM-GA showed increased expression of cytokines and growth factors that might mediate the effects of increased GA levels not only on pericyte migration but also on vascular permeability and angiogenesis. These data suggest that some effects elicited by GA might be produced by altering astrocyte-pericyte communication, rather than directly acting on pericytes. Importantly, GA-evoked alteration of capillary pericyte contractility may account for the reduced cerebral blood flow observed in GA-I patients.

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Abbreviations

BBB:

Blood-brain barrier

GA-I:

glutaric academia type I

GA:

glutaric acid

3-OHGA:

3-hydroxyglutaric acid

GCDH:

glutaryl-CoA dehydrogenase

PDGFRβ :

receptor β of the platelet derived growth factor

NG2:

neural/glial antigen 2

αSMA:

alpha smooth muscle actin

CM:

astrocyte conditioned media

CM-GA:

GA-treated astrocyte conditioned media

CM-C:

control astrocyte conditioned media

aCSF:

artificial cerebrospinal fluid

PI:

propidium iodide

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Funding

This study was funded by the Program for the Development of Basic Sciences (PEDECIBA) a joint program of the University of the Republic (UDELAR) and the Ministry of Education and Culture (MEC). E.I. received a Doctoral Fellowship from the National Agency for Innovation and Research (ANII) and grants to attend to Prof. Attwell’s lab from PEDECIBA and the Sectorial Comission for Scientific Research (CSIC, UDELAR). E.I.’s experiments in the Attwell lab were funded by a European Research Council grant to D.A. N.K. was supported by a BBSRC (UK) LIDo PhD studentship.

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Authors and Affiliations

  1. Neurobiología Celular y Molecular, Instituto Clemente Estable (IIBCE), 3318, Italia Av, 11600, Montevideo, Uruguay

    Eugenia Isasi & Silvia Olivera-Bravo

  2. Departmento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

    Eugenia Isasi

  3. Department of Neuroscience, Physiology and Pharmacology, University College London (UCL), London, UK

    Nils Korte & David Attwell

  4. Departmento de Fisiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

    Verónica Abudara

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  1. Eugenia Isasi
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  2. Nils Korte
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  5. Silvia Olivera-Bravo
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Correspondence to Silvia Olivera-Bravo.

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Ethical Statement

This study was performed in accordance with the Principles of Laboratory Animal Care, National Institute of Health of United States of America, NIH, publication no. 85-23 (2011 revision), and approved by the IIBCE Ethical Committee for the Care and Use of Laboratory Animals and from the National Committee for Laboratory Animal Care (CNEA) from Uruguay. All efforts were made to minimize suffering, discomfort and stress to the animals. The number of animals employed in this work was the necessary to produce reliable scientific data.

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Isasi, E., Korte, N., Abudara, V. et al. Glutaric Acid Affects Pericyte Contractility and Migration: Possible Implications for GA-I Pathogenesis. Mol Neurobiol 56, 7694–7707 (2019). https://doi.org/10.1007/s12035-019-1620-4

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