TY - JOUR
T1 - C9ORF72 repeat expansion affects the proteome of primary skin fibroblasts in ALS
AU - Lualdi, Marta
AU - Shafique, Adeena
AU - Pedrini, Edoardo
AU - Pieroni, Luisa
AU - Greco, Viviana
AU - Castagnola, Massimo
AU - Cucina, Giorgia
AU - Corrado, Lucia
AU - Di Pierro, Alice
AU - De Marchi, Fabiola
AU - Camillo, Lara
AU - Colombrita, Claudia
AU - D’Anca, Marianna
AU - Alberio, Tiziana
AU - D’Alfonso, Sandra
AU - Fasano, Mauro
PY - 2021
Y1 - 2021
N2 - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by pro-gressive degeneration of the corticospinal motor neurons, which ultimately leads to death. The repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) represents the most common genetic cause of ALS and it is also involved in the pathogenesis of other neurodegenerative disorders. To offer insights into C9ORF72-mediated pathogenesis, we quantitatively analyzed the proteome of patient-derived primary skin fibroblasts from ALS patients carrying the C9ORF72 mutation compared with ALS patients who tested negative for it. Differentially expressed proteins were identified, used to generate a protein-protein interaction network and subjected to a functional enrichment analysis to unveil altered molecular pathways. ALS patients were also compared with patients affected by frontotemporal dementia carrying the C9ORF72 repeat expansion. As a result, we demonstrated that the molecular pathways mainly altered in fibroblasts (e.g., protein homeostasis) mirror the alterations observed in C9ORF72-mutated neurons. Moreover, we highlighted novel molecular pathways (nuclear and mitochondrial transports, vesicle trafficking, mitochondrial bioenergetics, glucose metabolism, ER-phagosome crosstalk and Slit/Robo signaling pathway) which might be further investigated as C9ORF72-specific pathogenetic mechanisms. Data are available via ProteomeXchange with the identifier PXD023866.
AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by pro-gressive degeneration of the corticospinal motor neurons, which ultimately leads to death. The repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) represents the most common genetic cause of ALS and it is also involved in the pathogenesis of other neurodegenerative disorders. To offer insights into C9ORF72-mediated pathogenesis, we quantitatively analyzed the proteome of patient-derived primary skin fibroblasts from ALS patients carrying the C9ORF72 mutation compared with ALS patients who tested negative for it. Differentially expressed proteins were identified, used to generate a protein-protein interaction network and subjected to a functional enrichment analysis to unveil altered molecular pathways. ALS patients were also compared with patients affected by frontotemporal dementia carrying the C9ORF72 repeat expansion. As a result, we demonstrated that the molecular pathways mainly altered in fibroblasts (e.g., protein homeostasis) mirror the alterations observed in C9ORF72-mutated neurons. Moreover, we highlighted novel molecular pathways (nuclear and mitochondrial transports, vesicle trafficking, mitochondrial bioenergetics, glucose metabolism, ER-phagosome crosstalk and Slit/Robo signaling pathway) which might be further investigated as C9ORF72-specific pathogenetic mechanisms. Data are available via ProteomeXchange with the identifier PXD023866.
KW - Amyotrophic lateral sclerosis
KW - Proteomics
KW - Amyotrophic lateral sclerosis
KW - Proteomics
UR - http://hdl.handle.net/10807/194464
U2 - 10.3390/ijms221910385
DO - 10.3390/ijms221910385
M3 - Article
SN - 1661-6596
VL - 22
SP - 1
EP - 18
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
ER -