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Multi‐omics approach identifies differences between cranial and spinal motor neuron – A step towards understanding ALS
Author(s) -
Maity Shuvadeep,
An Disi,
Randleman Justin,
Iannitelli Dylan,
Mazzoni Esteban,
Vogel Christine
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03805
Subject(s) - amyotrophic lateral sclerosis , unfolded protein response , biology , neuroscience , motor neuron , context (archaeology) , endocytic cycle , endoplasmic reticulum , transcriptome , microbiology and biotechnology , spinal cord , cell , disease , gene , gene expression , genetics , medicine , pathology , endocytosis , paleontology
Amyotrophic Lateral Sclerosis (ALS) is an adult‐onset fatal neurodegenerative disease with a selective, highly progressive loss of both spinal and upper motor neurons. However, cranial motor neurons are much less sensitive and survive until the late stages of the disease. The inability of the cells to respond appropriately to Endoplasmic Reticulum (ER) stress is thought to be one of the major reasons for the ALS progression. ER stress is a condition that arises after the accumulation of misfolded proteins inside the ER and activates a repertoire of transcriptional and translational events collectively called unfolded protein response (UPR). In the context of ALS progression, the dynamics of transcriptomics and proteomic profile over time in the presence of ER stress conditions are poorly understood. Here, we established a condition where ER stress shows differential vulnerability of stem cell derived cranial (CrMN) and spinal motor (SpMN) neurons. Using high throughput quantitative omics approaches, we quantified >8,200 genes over time and found that subtle expression changes influence several pathways that are essential for cranial and spinal motor neuron function. We demonstrate that pathways related to overall protein turnover differ in these two cell lines. Specifically, we identified expression differences in Rab proteins that have not been recognized to‐date. These Rab proteins affect synaptic recycling, endocytic sorting, and autophagic flux. Further, we discovered a novel link between the core proteasome and endocytic pathways that potentially help CrMN to turn over proteins more efficiently than SpMN. Combined, these results illustrate new insights into the complex behavior and subtle differences between two motor neuron cell lines and provide new avenues towards therapeutic intervention. Support or Funding Information National Institute of General Medical Sciences (R01 GM113237), National Institute of General Medical Sciences (1R35GM127089‐01), Project ALS (A13‐0416)