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Dis Model Mech. 2018 Jan 29. pii: dmm.031625. doi: 10.1242/dmm.031625. [Epub ahead of print]

ALS lymphoblastoid cell lines as a considerable model to understand disease mechanisms.

Author information

1
Genomic and post-Genomic Center, "C. Mondino" National Neurological Institute, Pavia, Italy.
2
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
3
General Neurology Unit, "C. Mondino" National Neurological Institute, Pavia, Italy.
4
Department of Neurodiagnostics and Services, Laboratory of Clinicals and Chemicals Analysis (SMeL), , "C. Mondino" National Neurological Institute, Pavia, Italy.
5
Department of "Medicina Diagnostica e dei Servizi", IRCCS Policlinico San Matteo Foundation, Pavia, Italy.
6
Genomic and post-Genomic Center, "C. Mondino" National Neurological Institute, Pavia, Italy cristina.cereda@mondino.it.

Abstract

New evidences switch the hypothesis of amyotrophic lateral sclerosis (ALS) from a "neurocentric" to a "multisystemic" or "non-neurocentric" point of view. From 2006, we focused on the study of non-neural cells, patients' peripheral blood mononuclear cells (PMBCs) and lymphoblastoid cell lines (LCLs). Here, we characterized LCLs of sporadic ALS and patients carrying SOD1, TARDBP and FUS mutations to identify ALS biologically relevant signature, and whether and how mutations differentially affect ALS-linked pathways. Although LCLs are different from motor neurons (MNs), in LCLs we find out some features typical of degenerating MNs in ALS, i.e. protein aggregation and mitochondrial dysfunction. Moreover, different gene mutations otherwise affect ALS cellular mechanisms. TARDBP and FUS mutations imbalance mitochondrial dynamism toward an increased fusion, while sALS and SOD1 mutations mainly affect fission. As regard protein aggregation and/or mislocalization, TARDBP and SOD1 mutations show the presence of aggregates, while FUS mutation does not induce protein aggregation and/or mislocalization. Finally, all LCLs, independently from mutation, are not able to work in a condition of excessive energy request, suggesting that mitochondria from ALS patients are characterized by a significant metabolic defect. Taken together these data indicate that LCLs could be indicated as a valid cellular model in ALS research to study specific pathological pathways or to identify new ones.

KEYWORDS:

ALS model; LCLs; Mitochondria; Protein aggregation

PMID:
29419416
DOI:
10.1242/dmm.031625
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