CYP46A1 expression modulates mitochondrial function and integrity in Niemann-Pick type C disease
Elsa
Rodrigues1, 2*,
Daniela
Costa1,
Miguel
Moutinho1,
Maria
J.
Nunes1, 2,
Margarida
F.
Silva1, 2,
Rita
Mendes De Almeida1,
Andreia
N.
Carvalho1, 2,
Margarida
Castro-Caldas1, 3,
Maria
J.
Gama1, 2*,
Cecília
M.
Rodrigues1, 2 and
Nathalie
Cartier4
-
1
Research Institute for Medicines (iMed.ULisboa), Portugal
-
2
Faculdade de Farmácia, Universidade de Lisboa, Portugal
-
3
Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Portugal
-
4
INSERM U1169 Thérapie Génique, Génétique, épigénétique en Neurologie, Endocrinologie et Développement de l'enfant, France
Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The neuronal-specific CYP46A1 is responsible for the conversion of cholesterol into 24S-hydroxycholesterol, the major pathway for brain cholesterol elimination. Interestingly, increased expression of this hydroxylase improves cognition, while its reduction leads to a poor cognitive performance. Moreover, increasing amount of epidemiological, biochemical and molecular evidence suggests that CYP46A1 has a role in the pathogenesis or progression of neurodegenerative disorders, in which the up-regulation of this enzyme is clearly beneficial. We have identified that membrane cholesterol reduction by CYP46A1 is the necessary trigger to increased neuronal dendritic outgrowth and dendritic protrusion density, and to elicit in vitro and in vivo increase of synaptic proteins in crude synaptosomal fractions. Taking into account its role in cholesterol reduction and neuronal function, we hypothesized that CYP46A1 could be a potential therapeutic target in Niemann Pick Type C Disease (NPC). Human fibroblasts from NPC1 and NPC2 patients and stable NPC1-knockdown human neuroblastoma cells, were transduced with and an adenovirus encoding green fluorescent protein (GFP), or GFP and CYP46A1 and maintained for 96h. In NPC fibroblasts ectopic expression of CYP46A1 led to a reduction in cholesterol accumulation and sequestration in the late endosome/ lysosome compartment. Moreover, CYP46A1 expression partially restored the mRNA levels of cholesterol homeostasis related genes. In stable NPC1-knockdown SH-SY5Y cells, CYP46A1 ectopic expression, could also reduce cholesterol accumulation, and concomitantly rescue mitochondrial function and integrity, modulating mitochondria dynamics in favor of mitochondrial fusion. These data suggests that regulation of neuronal CYP46A1 might be a novel and promising strategy for NPC disease.
Acknowledgements
This work was supported by FEDER and national funds from Fundação para a Ciência e Tecnologia (FCT) (PTDC/MED-NEU/29455/2017, fellowships SFRH/BPD/95855/2013 (MJN) and SFRH/BPD/98023/2013 (ANC)), Bolsa de Investigação da Sociedade Portuguesa de Doenças Metabólicas (SPDM), and BrainVectis Technologies.
Keywords:
CYP46A1,
brain cholesterol,
Niemman Pick type C,
Mitochondria,
Neurode generation
Conference:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019.
Presentation Type:
Oral presentation
Topic:
Rare Disorders
Citation:
Rodrigues
E,
Costa
D,
Moutinho
M,
Nunes
MJ,
Silva
MF,
Mendes De Almeida
R,
Carvalho
AN,
Castro-Caldas
M,
Gama
MJ,
Rodrigues
CM and
Cartier
N
(2019). CYP46A1 expression modulates mitochondrial function and integrity in Niemann-Pick type C disease.
Front. Cell. Neurosci.
Conference Abstract:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019).
doi: 10.3389/conf.fncel.2019.01.00030
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Received:
28 Feb 2019;
Published Online:
27 Sep 2019.
*
Correspondence:
PhD. Elsa Rodrigues, Research Institute for Medicines (iMed.ULisboa), Lisboa, Portugal, Elsa.Rodrigues@ff.ulisboa.pt
PhD. Maria J Gama, Research Institute for Medicines (iMed.ULisboa), Lisboa, Portugal, mjgama@ff.ulisboa.pt