, Volume 19, Issue 3, pp 189–204 | Cite as

FUS(1-359) transgenic mice as a model of ALS: pathophysiological and molecular aspects of the proteinopathy

  • Sergei Y. Funikov
  • Alexander P. Rezvykh
  • Pavel V. Mazin
  • Alexey V. Morozov
  • Andrey V. Maltsev
  • Maria M. Chicheva
  • Ekaterina A. Vikhareva
  • Mikhail B. Evgen’evEmail author
  • Aleksey A. Ustyugov
Original Article


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that leads to the eventual death of motor neurons. Described cases of familial ALS have emphasized the significance of protein misfolding and aggregation of two functionally related proteins, FUS (fused in sarcoma) and TDP-43, implicated in RNA metabolism. Herein, we performed a comprehensive analysis of the in vivo model of FUS-mediated proteinopathy (ΔFUS(1-359) mice). First, we used the Noldus CatWalk system and confocal microscopy to determine the time of onset of the first clinical symptoms and the appearance of FUS-positive inclusions in the cytoplasm of neuronal cells. Second, we applied RNA-seq to evaluate changes in the gene expression profile encompassing the pre-symptomatic and the symptomatic stages of disease progression in motor neurons and the surrounding microglia of the spinal cord. The resulting data show that FUS-mediated proteinopathy is virtually asymptomatic in terms of both the clinical symptoms and the molecular aspects of neurodegeneration until it reaches the terminal stage of disease progression (120 days from birth). After this time, the pathological process develops very rapidly, resulting in the formation of massive FUS-positive inclusions accompanied by a transcriptional “burst” in the spinal cord cells. Specifically, it manifests in activation of a pro-inflammatory phenotype of microglial cells and malfunction of acetylcholine synapse transmission in motor neurons. Overall, we assume that the highly reproducible course of the pathological process, as well as the described accompanying features, makes ΔFUS(1-359) mice a convenient model for testing potential therapeutics against proteinopathy-induced decay of motor neurons.


ALS Transgenic mouse model FUS Proteinopathy RNA-seq Gene expression 



We thank Dr. Vladimir Buchman for critical comments on the manuscript. We are grateful to Vladimir Popenko for technical assistance with confocal microscopy and Tom Hurt for language improvements. We thank Nailia Khasbiullina from Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS for many helpful recommendations on the interpretation of results. Facilities of the Bioresource Collection of IPAC RAS (No. 0090-2017-0016) were used to maintain animals for CatWalk data collection using equipment of the Center for Collective Use IPAC RAS. Transgenic animal research was carried out according to the State Research Program assignment for IPAC RAS (No. 0090-2017-0019). RNA sequencing was performed using the equipment of the Engelhardt Institute of Molecular Biology RAS “Genome” center (

Funding information

Life expectancy and immunohistochemical analysis studies were supported by the RFBR (№16-04-01089А). Transcriptome profile analysis was supported by the Russian Science Foundation (RSF) grant №14-50-00060. This work was supported by the Program of Fundamental Research for State Academies for the years 2013-2020 (№01201363817).

Supplementary material

10048_2018_553_Fig7_ESM.png (227 kb)
Supplemental figure S1

Multidimensional scaling (MDS) was performed using one minus the Spearman correlation coefficient between z-scores for all mice (WT are shown in green, ΔFUS(1-359) are in red). (PNG 227 kb)

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High resolution image (TIF 315 kb)
10048_2018_553_Fig8_ESM.png (233 kb)
Supplemental figure S2

Analysis of similarities and differences in gene expression profiles among the biological replicates of ΔFUS(1-359) and wild-type mice. A) Heatmap based on the pairwise Spearman correlation of gene expression with the use of the Euclidean distance and complete linkage as distance measures and clustering methods, respectively. B) Two-dimensional plot of the first two principal components calculated by PCA of the transposed log-transformed RPM values of gene expression. (PNG 233 kb)

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High resolution image (TIF 631 kb)
10048_2018_553_Fig9_ESM.png (30 kb)
Supplemental figure S3

Chemokine signaling pathway at the symptomatic stage (120 days) of ΔFUS(1-359) mice based on KEGG analysis IDs, color-coded by expression level. (PNG 30 kb)

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High resolution image (TIF 58 kb)
10048_2018_553_Fig10_ESM.png (46 kb)
Supplemental figure S4

NF-kB signaling pathway at the symptomatic stage (120 days) of ΔFUS(1-359) mice based on KEGG analysis IDs, color-coded by expression level. (PNG 45 kb)

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High resolution image (TIF 74 kb)
10048_2018_553_Fig11_ESM.png (50 kb)
Supplemental figure S5

Cell adhesion molecules at the symptomatic stage (120 days) of ΔFUS(1-359) mice based on KEGG analysis IDs, color-coded by expression level. (PNG 50 kb)

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High resolution image (TIF 90 kb)
10048_2018_553_Fig12_ESM.png (23 kb)
Supplemental figure S6

Antigen processing and presentation at the symptomatic stage (120 days) of ΔFUS(1-359) mice based on KEGG analysis IDs, color-coded by expression level. (PNG 22 kb)

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High resolution image (TIF 51 kb)
10048_2018_553_Fig13_ESM.png (34 kb)
Supplemental figure S7

Toll-like receptor signaling pathway at the symptomatic stage (120 days) of ΔFUS(1-359) mice based on KEGG analysis IDs, color-coded by expression level. (PNG 33 kb)

10048_2018_553_MOESM7_ESM.tif (60 kb)
High resolution image (TIF 60 kb)
10048_2018_553_Fig14_ESM.png (23 kb)
Supplemental figure S8

B cell receptor signaling pathway at the symptomatic stage (120 days) of ΔFUS(1-359) mice based on KEGG analysis IDs, color-coded by expression level. (PNG 23 kb)

10048_2018_553_MOESM8_ESM.tif (51 kb)
High resolution image (TIF 51 kb)
10048_2018_553_Fig15_ESM.png (67 kb)
Supplemental figure S9

Boxplot of Trem2 expression in the spinal cord of ΔFUS(1-359) mice. * indicates P ≤ 0.05. (PNG 67 kb)

10048_2018_553_MOESM9_ESM.tif (129 kb)
High resolution image (TIF 128 kb)
10048_2018_553_Fig16_ESM.png (1.3 mb)
Supplemental figure S10

Comparative analysis of ΔFUS(1-359) and SOD1G93A microglia transcriptome data. A) PCA-plot of FUS(1-359) and SOD1G93A microglia at the symptomatic stage (120 days for FUS(1-359) and 130 days for SOD1G93A) of disease progression. B) Heatmap on the top illustrates fold change of gene expression between the symptomatic and pre-symptomatic stages of ΔFUS(1-359) and SOD1G93A microglia. On the bottom the expression levels of genes at the terminal (symptomatic) stage are shown. Normalization type is counts per million (CPM). (PNG 1337 kb)

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High resolution image (TIF 2268 kb)
10048_2018_553_Fig17_ESM.png (29 kb)
Supplemental figure S11

Steroid biosynthesis at the symptomatic stage (120 days) of ΔFUS(1-359) mice based on KEGG analysis IDs, color-coded by expression level. (PNG 28 kb)

10048_2018_553_MOESM11_ESM.tif (56 kb)
High resolution image (TIF 55 kb)
10048_2018_553_Fig18_ESM.png (38 kb)
Supplemental figure S12

Cholinergic synapse at the symptomatic stage (120 days) of ΔFUS(1-359) mice based on KEGG analysis IDs, color-coded by expression level. (PNG 38 kb)

10048_2018_553_MOESM12_ESM.tif (63 kb)
High resolution image (TIF 63 kb)
10048_2018_553_Fig19_ESM.png (36 kb)
Supplemental figure S13

Amyotrophic lateral sclerosis pathway at the symptomatic stage (120 days) of ΔFUS(1-359) mice based on KEGG analysis IDs, color-coded by expression level. (PNG 36 kb)

10048_2018_553_MOESM13_ESM.tif (67 kb)
High resolution image (TIF 67 kb)
10048_2018_553_Fig20_ESM.png (408 kb)
Supplemental figure S14

Changes in alternative splicing in the spinal cord of ΔFUS(1-359). A) MDS plot for all samples based on cassette exons (CE). Transgenic and wild-type mice are shown in red and green, respectively; different ages are shown by different point size. B) Number of statistically significant AS events for different pairwise comparisons; different AS event types are shown by different colors. Cassette exons (CE), alternative donor (AD) or alternative acceptor (AA) sites, and retained introns (RI). C) Correlation of dPSI between the asymptomatic (60 days) and the symptomatic (120 days) of ΔFUS(1-359) mice (x-axis) and dPSI between the symptomatic ΔFUS(1-359) mice and wild-type mice of the same age (120 days) (y-axis). Only events significant in both comparisons are shown. Different AS types are shown by different colors. D) Distribution of dPSI of significantly changes microexons (red, N = 62) and other exons (gray, N = 343). (PNG 408 kb)

10048_2018_553_MOESM14_ESM.tif (659 kb)
High resolution image (TIF 658 kb)
10048_2018_553_MOESM15_ESM.xls (172 kb)
Supplemental table S1 Differentially expressed genes in the spinal cord of ΔFUS(1-359) mice sorted by microglia, motoneurons and non-specific groups. (XLS 171 kb)
10048_2018_553_MOESM16_ESM.xls (20 kb)
Supplemental table S2 GO analysis of genes exhibiting alternative splicing events at the symptomatic stage in the spinal cord of ΔFUS(1-359) mice. (XLS 20 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Sergei Y. Funikov
    • 1
  • Alexander P. Rezvykh
    • 1
  • Pavel V. Mazin
    • 2
    • 3
    • 4
  • Alexey V. Morozov
    • 1
  • Andrey V. Maltsev
    • 5
  • Maria M. Chicheva
    • 5
  • Ekaterina A. Vikhareva
    • 5
  • Mikhail B. Evgen’ev
    • 1
    Email author
  • Aleksey A. Ustyugov
    • 5
  1. 1.Engelhardt Institute of Molecular Biology RASMoscowRussian Federation
  2. 2.Center for Data-Intensive Biomedicine and BiotechnologySkolkovo Institute of Science and TechnologyMoscowRussia
  3. 3.Institute for Information Transmission Problems (Kharkevich Institute) RASMoscowRussian Federation
  4. 4.Faculty of Computer ScienceHigher School of EconomicsMoscowRussian Federation
  5. 5.Institute of Physiologically Active Compounds RASChernogolovkaRussian Federation

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