Research Paper Volume 11, Issue 22 pp 10338—10355

GBA mutation promotes early mitochondrial dysfunction in 3D neurosphere models

Constanza Morén 1, 2, 3, *, , Diana Luz Juárez-Flores 1, 2, *, , Kai-Yin Chau 3, , Matthew Gegg 3, , Glòria Garrabou 1, 2, , Ingrid González-Casacuberta 1, 2, , Mariona Guitart-Mampel 1, 2, , Eduardo Tolosa 4, , María José Martí 4, , Francesc Cardellach 1, 2, , Anthony Henry Vernon Schapira 3, ,

  • 1 Cellex, IDIBAPS, University of Barcelona-Hospital Clínic of Barcelona, Barcelona 08036, Spain
  • 2 Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), Madrid 28029, Spain
  • 3 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London NW3 2PF, UK
  • 4 Neurology Department, Hospital Clínic of Barcelona, Barcelona 08036, Spain
* Equal contribution

received: June 21, 2019 ; accepted: November 8, 2019 ; published: November 21, 2019 ;
How to Cite

Copyright © 2019 Morén et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Glucocerebrosidase (GBA) mutations are the most important genetic risk factor for the development of Parkinson disease (PD). GBA encodes the lysosomal enzyme glucocerebrosidase (GCase). Loss-of-GCase activity in cellular models has implicated lysosomal and mitochondrial dysfunction in PD disease pathogenesis, although the exact mechanisms remain unclear. We hypothesize that GBA mutations impair mitochondria quality control in a neurosphere model.

We have characterized mitochondrial content, mitochondrial function and macroautophagy flux in 3D-neurosphere-model derived from neural crest stem cells containing heterozygous and homozygous N370SGBA mutations, under carbonyl cyanide-m-chlorophenyl-hydrazine (CCCP)- induced mitophagy.

Our findings on mitochondrial markers and ATP levels indicate that mitochondrial accumulation occurs in mutant N370SGBA neurospheres under basal conditions, and clearance of depolarised mitochondria is impaired following CCCP-treatment. A significant increase in TFEB-mRNA levels, the master regulator of lysosomal and autophagy genes, may explain an unchanged macroautophagy flux in N370SGBA neurospheres. PGC1α-mRNA levels were also significantly increased following CCCP-treatment in heterozygote, but not homozygote neurospheres, and might contribute to the increased mitochondrial content seen in cells with this genotype, probably as a compensatory mechanism that is absent in homozygous lines.

Mitochondrial impairment occurs early in the development of GCase-deficient neurons. Furthermore, impaired turnover of depolarised mitochondria is associated with early mitochondrial dysfunction.

In summary, the presence of GBA mutation may be associated with higher levels of mitochondrial content in homozygous lines and lower clearance of damaged mitochondria in our neurosphere model.


CM: Constanza Morén; DJ: Diana Luz Juárez-Flores; KYC: Kai-Yin Chau; MG: Matt Gegg; GG: Glòria Garrabou; IG: Ingrid González-Casacuberta; MG: Mariona Guitart-Mampel; ET: Eduardo Tolosa; MJ: Maria Josep Martí; FC: Francesc Cardellach; AS: Anthony Henry V Schapira.