IGF-1 treatment causes unique transcriptional response in neurons from individuals with idiopathic autism.

Autor: Linker SB; The Salk Institute, Laboratory of Genetics, La Jolla, CA, 92037, USA., Mendes APD; The Salk Institute, Laboratory of Genetics, La Jolla, CA, 92037, USA., Marchetto MC; The Salk Institute, Laboratory of Genetics, La Jolla, CA, 92037, USA. marchetto@salk.edu.; Department of Anthropology, University of California, San Diego, La Jolla, CA, 92037, USA. marchetto@salk.edu.
Jazyk: angličtina
Zdroj: Molecular autism [Mol Autism] 2020 Jun 26; Vol. 11 (1), pp. 55. Date of Electronic Publication: 2020 Jun 26.
DOI: 10.1186/s13229-020-00359-w
Abstrakt: Background: Research evidence accumulated in the past years in both rodent and human models for autism spectrum disorders (ASD) have established insulin-like growth factor 1 (IGF-1) as one of the most promising ASD therapeutic interventions to date. ASD is phenotypically and etiologically heterogeneous, making it challenging to uncover the underlying genetic and cellular pathophysiology of the condition; and to efficiently design drugs with widespread clinical benefits. While IGF-1 effects have been comprehensively studied in the literature, how IGF-1 activity may lead to therapeutic recovery in the ASD context is still largely unknown.
Methods: In this study, we used a previously characterized neuronal population derived from induced pluripotent stem cells (iPSC) from neurotypical controls and idiopathic ASD individuals to study the transcriptional signature of acutely and chronically IGF-1-treated cells.
Results: We present a comprehensive list of differentially regulated genes and molecular interactions resulting from IGF-1 exposure in developing neurons from controls and ASD individuals. Our results indicate that IGF-1 treatment has a different impact on neurons from ASD patients compared to controls. Response to IGF-1 treatment in neurons derived from ASD patients was heterogeneous and correlated with IGF-1 receptor expression, indicating that IGF-1 response may have responder and non-responder distinctions across cohorts of ASD patients. Our results suggest that caution should be used when predicting the effect of IGF-1 treatment on ASD patients using neurotypical controls. Instead, IGF-1 response should be studied in the context of ASD patients' neural cells.
Limitations: The limitation of our study is that our cohort of eight sporadic ASD individuals is comorbid with macrocephaly in childhood. Future studies will address weather downstream transcriptional response of IGF-1 is comparable in non-macrocephalic ASD cohorts.
Conclusions: The results presented in this study provide an important resource for researchers in the ASD field and underscore the necessity of using ASD patient lines to explore ASD neuronal-specific responses to drugs such as IGF-1. This study further helps to identify candidate pathways and targets for effective clinical intervention and may help to inform clinical trials in the future.
Databáze: MEDLINE
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