Cytoplasmic aggregates and nuclear depletion of the ubiquitous RNA-binding protein TDP-43 have been described in the autoptic brain tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD) patients and both TDP-43 loss-of-function and gain-of-function mechanisms seem to contribute to the neurodegenerative process. Among the wide array of RNA targets, TDP-43 regulates progranulin (GRN) mRNA stability and sortilin (SORT1) splicing. Progranulin is a secreted neurotrophic and neuro-immunomodulatory factor whose endocytosis and delivery to the lysosomes are regulated by the neuronal receptor sortilin. Moreover, GRN loss-of-function mutations are causative of a subset of FTLD cases showing TDP-43 pathological aggregates. Here we show that TDP-43 loss-of-function differently affects the progranulin–sortilin axis in murine and human neuronal cell models. We demonstrated that although TDP-43 binding to GRN mRNA occurs similarly in human and murine cells, upon TDP-43 depletion, a different control of sortilin splicing and protein content may determine changes in extracellular progranulin uptake that account for increased or unchanged secreted protein in murine and human cells, respectively. As targeting the progranulin–sortilin axis has been proposed as a therapeutic approach for GRN-FTLD patients, the inter-species differences in TDP-43-mediated regulation of this pathway must be considered when translating studies from animal models to patients.
Inter-species differences in regulation of the progranulin–sortilin axis in TDP-43 cell models of neurodegeneration / V. Gumina, E. Onesto, C. Colombrita, A. Maraschi, V. Silani, A. Ratti. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - 20:23(2019 Nov 22), pp. 5866.1-5866.16.
|Titolo:||Inter-species differences in regulation of the progranulin–sortilin axis in TDP-43 cell models of neurodegeneration|
RATTI, ANTONIA (Corresponding)
|Parole Chiave:||ALS; FTLD; Progranulin; Sortilin; TDP-43|
|Settore Scientifico Disciplinare:||Settore MED/26 - Neurologia|
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
|Data di pubblicazione:||22-nov-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3390/ijms20235866|
|Appare nelle tipologie:||01 - Articolo su periodico|