Molecular Neurobiology

, Volume 56, Issue 10, pp 6777–6791 | Cite as

Wnt Signaling Alterations in the Human Spinal Cord of Amyotrophic Lateral Sclerosis Cases: Spotlight on Fz2 and Wnt5a

  • Carlos González-Fernández
  • Pau Gonzalez
  • Pol Andres-Benito
  • Isidro Ferrer
  • Francisco Javier RodríguezEmail author


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no cure, and elucidation of the mechanisms mediating neuronal death in this neuropathology is crucial to develop effective treatments. It has recently been demonstrated in animal models that the Wnt family of proteins is involved in this neuropathology, although its potential involvement in case of humans is almost unknown. We analyzed the expression of Wnt signaling components in healthy and ALS human spinal cords by quantitative RT-PCR, and we found that most Wnt ligands, modulators, receptors, and co-receptors were expressed in healthy controls. Moreover, we observed clear alterations in the mRNA expression of different components of this family of proteins in human spinal cord tissue from ALS cases. Specifically, we detected a significant increase in the mRNA levels of Wnt3, Wnt4, Fz2, and Fz8, together with several non-significant increases in the mRNA expression of other genes such as Wnt2b, Wnt5a, Fz3, Lrp5, and sFRP3. Based on these observations and on previous reports of studies performed in animal models, we evaluated with immunohistochemistry the protein expression patterns of Fz2 and Fz5 receptors and their main ligand Wnt5a in control samples and ALS cases. No substantial changes were observed in Fz5 protein expression pattern in ALS samples. However, we detected an increase in the amount of Fz2+ astrocytes in the borderline between gray and white matter at the ventral horn in ALS samples. Finally, Wnt5a expression was observed in neurons and astrocytes in both control and ALS samples, although Wnt5a immunolabeling in astroglial cells was significantly increased in ALS spinal cords in the same region where changes in Fz2 were observed. Altogether, these observations strongly suggest that the Wnt family of proteins, and more specifically Fz2 and Wnt5a, might be involved in human ALS pathology.


Wnt Frizzled ALS Human Spinal cord 



We would like to thank Sandra Vázquez and Virginia Pérez for their outstanding technical help, as well as Dr. Daniel García-Ovejero from the Group of Neuroinflammation for sharing with us his deep knowledge and methodology on the human histology used in the study. We are extremely grateful to all individuals who agreed to donate their tissues to research.

Funding information

This work was funded by the Fondo de Investigaciones Sanitarias (FIS) (Grant PI12-02895, co-funded by Fondo Europeo de Desarrollo Regional (FEDER)) from the Instituto de Salud Carlos III (ISCIII).

Compliance with Ethical Standards

Statement on the Welfare of Animals

This article does not contain any studies with animals performed by any of the authors.

Conflict of Interest

The authors declare they have no conflict of interests.

Statement on Sample Extraction and Processing from ALS Patients

Postmortem samples from all individual participants were obtained with written informed consent prior to inclusion in the study, which has been conducted according to 1964 Declaration of Helsinki principles and its later amendments, following the ethical rule of the Hospital Universitari de Bellvitge (Spain) and according to the Directive 2004/23/EC of the European Parliament and of the Council. All samples were handled after approval by the Clinical Research Ethical Committee (CEIC) in Toledo (Spain) and in accordance with Spanish law and International Guidelines (LOPD 15/1999; RD 1720/2007; 1964 Helsinki declaration and its later amendments or comparable ethical standards).

Supplementary material

12035_2019_1547_Fig6_ESM.png (1.4 mb)
Fig. S1

Pre-incubation of Fz2, Fz5 and Wnt5a antibodies with their corresponding blocking peptides. The pre-incubation was performed with 10-fold weight/weight excess for Fz2 and Fz5, and 20-fold weight/weight excess for Wnt5a. Representative images showing the immunostaining blockade of Fz2 (b1- b3), Fz5 (a1- a3) and Wnt5a (c1- c3). Scale bars = 100μm. (PNG 1436 kb)

12035_2019_1547_MOESM1_ESM.tif (9.6 mb)
High Resolution image (TIF 9781 kb)


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Authors and Affiliations

  1. 1.Molecular Neurology GroupHospital Nacional de Parapléjicos (HNP)ToledoSpain
  2. 2.Department of Pathology and Experimental Therapeutics, Service of Pathologic Anatomy, IDIBELL-Bellvitge University Hospital, CIBERNED, Hospitalet de LlobregatUniversity of BarcelonaBarcelonaSpain

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