Analysis of PrPC/STI1 signaling and possible therapeutic role in Amyotrophic Lateral Sclerosis

• Grant number: 13/26097-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2014
• End date: November 30, 2016
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Vilma Regina Martins
• Grantee: Gabriela Pintar de Oliveira
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated research grant: 09/14027-2 - Mechanisms associated with the function of prion protein and its ligand STI1/Hop: therapeutic approaches, AP.TEM

Abstract

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset and fast progression neurodegenerative disease promoted by the loss of motor neurons, leading to death within 2-5 years. Glial cells have been implicated in the neuronal death by releasing toxic factors or by loosing physiological functions. The interaction between the prion protein (PrPC) in the neuronal surface and its ligand STI1, released by astrocytes in extracellular vesicles, promotes protection to both cell types. Thus, the signaling PrPC/STI1 was described to be important to astrocyte-neuron communication and it this complex might have a therapeutic role in ALS.In this study, the expressions of PrPC and STI1 will be evaluated in different ages of the SOD1G93A transgenic mice, carrying the human mutant SOD1, which is the most employed animal model in the ALS research. Also, STI1 will be quantified in extracellular vesicles released by SOD1G93A astrocytes when compared to controls. The establishment of co-cultures will allow evaluating the influence of a STI1 peptide, that mimics the bond site to PrPC, over the SOD1G93A and wild-type motor neurons death induced by SOD1G93A astrocytes. Once confirmed the neuroprotection promoted by the peptide in this model, its effect will be evaluated in vivo in the SOD1G93A transgenic mouse. Furthermore, transgenic mouse overexpressing the STI1 protein (TgA) will be mated with the SOD1G93A and the disease course will be evaluated. This study might contribute to the identification of therapeutic approaches to this devastating disease.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SOUSA DE LACERDA, TONIELLI CRISTINA; COSTA-SILVA, BRUNO; GIUDICE, FERNANDA SALGUEIREDO; SALLES DIAS, MARCOS VINICIOS; DE OLIVEIRA, GABRIELA PINTAR; TEIXEIRA, BIANCA LUISE; DOS SANTOS, TIAGO GOSS; MARTINS, VILMA REGINA. Prion protein binding to HOP modulates the migration and invasion of colorectal cancer cells. CLINICAL & EXPERIMENTAL METASTASIS, v. 33, n. 5, p. 441-451, JUN 2016. (12/23285-8, 13/26097-0, 10/19200-1, 09/14027-2, 11/18718-0, 11/20853-2)

LANDEMBERGER, MICHELE CHRISTINE; DE OLIVEIRA, GABRIELA PINTAR; MACHADO, CLEITON FAGUNDES; GOLLOB, KENNETH JOHN; MARTINS, VILMA REGINA. Loss of STI1-mediated neuronal survival and differentiation in disease-associated mutations of prion protein. Journal of Neurochemistry, v. 145, n. 5, p. 409-416, JUN 2018. (13/26097-0)