TY - JOUR
T1 - β-catenin aggregation in models of ALS motor neurons
T2 - GSK3β inhibition effect and neuronal differentiation
AU - Pinto, Cristina
AU - Medinas, Danilo B.
AU - Fuentes-Villalobos, Francisco
AU - Maripillán, Jaime
AU - Castro, Ariel F.
AU - Martínez, Agustín D.
AU - Osses, Nelson
AU - Hetz, Claudio
AU - Henríquez, Juan P.
N1 - Funding Information:
We thank Drs. Brigitte van Zundert, Lisette Leyton, Federico Bátiz, Luis Aguayo, Teresa Caprile, Christian Peters, and Viviana Pérez for their contribution to these studies. We also thank Pablo Rozas for technical assistance. This work was funded by research grants from Fondo Nacional de Desarrollo Científico y Tecnológico Chile (FONDECYT) 1130321, 1170614 (to JPH), 1140549 (to CH), 1160731 (to AFC), 1171240 (to ADM) and 11150579 (to DM). Additionally, this work was funded by Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias Chile (FONDAP) program 15150012, the Millennium Institute Chile P09-015-F, Fondo de Fomento al Desarrollo Científico y Tecnológico Chile (FONDEF) ID16I10223 and D11E1007, CONICYT-Brazil 441921/2016-7, the ALS Therapy Alliance 2014-F-059, the Muscular Dystrophy Association 382453, and the ALSRP Therapeutic Idea Award 81XWH-16-1-0112, the US Office of Naval Research-Global (ONR-G) N62909-16-1-2003, the US Air Force Office of Scientific Research FA9550-16-1-0384, the Michael J. Fox Foundation for Parkinson's Research – Target Validation grant no. 9277 (to CH), Muscular Dystrophy Association 575897, ALS Association 468 (to DM) and The Centro Interdisciplinario de Neurociencia de Valparaiso Millennium Institute (P09-022-F) (to ADM).
Funding Information:
We thank Drs. Brigitte van Zundert, Lisette Leyton, Federico Bátiz, Luis Aguayo, Teresa Caprile, Christian Peters, and Viviana Pérez for their contribution to these studies. We also thank Pablo Rozas for technical assistance. This work was funded by research grants from Fondo Nacional de Desarrollo Científico y Tecnológico Chile (FONDECYT) 1130321 , 1170614 (to JPH), 1140549 (to CH), 1160731 (to AFC), 1171240 (to ADM) and 11150579 (to DM). Additionally, this work was funded by Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias Chile (FONDAP) program 15150012 , the Millennium Institute Chile P09-015-F, Fondo de Fomento al Desarrollo Científico y Tecnológico Chile (FONDEF) ID16I10223 and D11E1007 , CONICYT-Brazil 441921/2016-7, the ALS Therapy Alliance 2014-F-059, the Muscular Dystrophy Association 382453 , and the ALSRP Therapeutic Idea Award 81XWH-16-1-0112, the US Office of Naval Research-Global (ONR-G) N62909-16-1-2003, the US Air Force Office of Scientific Research FA9550-16-1-0384, the Michael J. Fox Foundation for Parkinson's Research – Target Validation grant no. 9277 (to CH), Muscular Dystrophy Association 575897 , ALS Association 468 (to DM) and The Centro Interdisciplinario de Neurociencia de Valparaiso Millennium Institute ( P09-022-F ) (to ADM).
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/10
Y1 - 2019/10
N2 - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron death. A 20% of familial ALS cases are associated with mutations in the gene coding for superoxide dismutase 1 (SOD1). The accumulation of abnormal aggregates of different proteins is a common feature in motor neurons of patients and transgenic ALS mice models, which are thought to contribute to disease pathogenesis. Developmental morphogens, such as the Wnt family, regulate numerous features of neuronal physiology in the adult brain and have been implicated in neurodegeneration. β-catenin is a central mediator of both, Wnt signaling activity and cell-cell interactions. We previously reported that the expression of mutant SOD1 in the NSC34 motor neuron cell line decreases basal Wnt pathway activity, which correlates with cytosolic β-catenin accumulation and impaired neuronal differentiation. In this work, we aimed a deeper characterization of β-catenin distribution in models of ALS motor neurons. We observed extensive accumulation of β-catenin supramolecular structures in motor neuron somas of pre-symptomatic mutant SOD1 mice. In cell-cell appositional zones of NSC34 cells expressing mutant SOD1, β-catenin displays a reduced co-distribution with E-cadherin accompanied by an increased association with the gap junction protein Connexin-43; these findings correlate with impaired intercellular adhesion and exacerbated cell coupling. Remarkably, pharmacological inhibition of the glycogen synthase kinase-3β (GSK3β) in both NSC34 cell lines reverted both, β-catenin aggregation and the adverse effects of mutant SOD1 expression on neuronal differentiation. Our findings suggest that early defects in β-catenin distribution could be an underlying factor affecting the onset of neurodegeneration in familial ALS.
AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron death. A 20% of familial ALS cases are associated with mutations in the gene coding for superoxide dismutase 1 (SOD1). The accumulation of abnormal aggregates of different proteins is a common feature in motor neurons of patients and transgenic ALS mice models, which are thought to contribute to disease pathogenesis. Developmental morphogens, such as the Wnt family, regulate numerous features of neuronal physiology in the adult brain and have been implicated in neurodegeneration. β-catenin is a central mediator of both, Wnt signaling activity and cell-cell interactions. We previously reported that the expression of mutant SOD1 in the NSC34 motor neuron cell line decreases basal Wnt pathway activity, which correlates with cytosolic β-catenin accumulation and impaired neuronal differentiation. In this work, we aimed a deeper characterization of β-catenin distribution in models of ALS motor neurons. We observed extensive accumulation of β-catenin supramolecular structures in motor neuron somas of pre-symptomatic mutant SOD1 mice. In cell-cell appositional zones of NSC34 cells expressing mutant SOD1, β-catenin displays a reduced co-distribution with E-cadherin accompanied by an increased association with the gap junction protein Connexin-43; these findings correlate with impaired intercellular adhesion and exacerbated cell coupling. Remarkably, pharmacological inhibition of the glycogen synthase kinase-3β (GSK3β) in both NSC34 cell lines reverted both, β-catenin aggregation and the adverse effects of mutant SOD1 expression on neuronal differentiation. Our findings suggest that early defects in β-catenin distribution could be an underlying factor affecting the onset of neurodegeneration in familial ALS.
KW - ALS
KW - Accumulation
KW - Differentiation
KW - GSK3β inhibition
KW - Motor neuron
KW - β-Catenin
UR - http://www.scopus.com/inward/record.url?scp=85067231199&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2019.104497
DO - 10.1016/j.nbd.2019.104497
M3 - Article
C2 - 31176720
AN - SCOPUS:85067231199
VL - 130
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
M1 - 104497
ER -