Integrated analysis of transcriptomic and proteomic alterations in mouse models of ALS/FTD identify early metabolic adaptions with similarities to mitochondrial dysfunction disorders

Abstract

Objective

Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD.

Methods

By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage.

Results

In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology.

Conclusions

Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.

Keywords:

• Amyotrophic lateral sclerosis (ALS)
• frontotemporal dementia (FTD)
• bioinformatics
• master regulator analysis
• mitochondrial dysfunction
• lipid metabolism

Acknowledgements

We wish to thank Ms. Christiane Bartling-Kirsch (DZNE) for her technical assistance.

Authors’ contributions

AM, NK and DG analyzed and interpreted the data, and drafted the manuscript. OW, AR, DG, IFP, ILF, CF, ELC, JJ, AP, LW, IW, LH, MH, AGM, ETD, DM, IA, DL acquired the data. AR, DG, JJ, AP, LW, NMC analyzed and interpreted the data. DB, NMC and JHMP acquired funding, supervised the project, interpreted the data and drafted the manuscript. All authors have read and approved the final version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets supporting the conclusions of this article are available in the Gene Expression Omnibus (GEO) repository [GSE196482, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE196482] and on the ProteomeXchange Consortium via the PRIDE partner repository [PXD030210, http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD030210].

Additional information

Funding

This research was supported by grants from Science Foundation Ireland (17/COEN/3474 and SFI FutureNeuro Research Center 16/RC/3948 co-funded under the European Regional Development Fund and by FutureNeuro industry partners) to JHMP, and the DZNE institutional budget, the CoEN (Carbon-Model, 3018) initiative and the Helmholtz cross-program topic “Aging and Metabolic Programming (AMPro)” to DB. DB is a member of the DFG Cluster of Excellence ImmunoSensation funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC2151 – 390873048. DB, NMCC and JHMP are members of the Mitochondrial Dysfunction in Parkinson’s Consortium (PD-MitoQUANT). PD-MitoQUANT has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 821522. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.