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Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice.

Shelkovnikova TA, Peters OM, Deykin AV, Connor-Robson N, Robinson H, Ustyugov AA, Bachurin SO, Ermolkevich TG, Goldman IL, Sadchikova ER, Kovrazhkina EA, Skvortsova VI, Ling SC, Da Cruz S, Parone PA, Buchman VL, Ninkina NN - J. Biol. Chem. (2013)

Bottom Line: Dysfunction of two structurally and functionally related proteins, FUS and TAR DNA-binding protein of 43 kDa (TDP-43), implicated in crucial steps of cellular RNA metabolism can cause amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases.To address this question, we designed a variant of FUS, FUS 1-359, which is predominantly cytoplasmic, highly aggregate-prone, and lacks a region responsible for RNA recognition and binding.These pathological changes cause abrupt development of a severe motor phenotype at the age of 2.5-4.5 months and death of affected animals within several days of onset.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, Cardiff University, Cardiff, Wales, United Kingdom.

ABSTRACT
Dysfunction of two structurally and functionally related proteins, FUS and TAR DNA-binding protein of 43 kDa (TDP-43), implicated in crucial steps of cellular RNA metabolism can cause amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases. The proteins are intrinsically aggregate-prone and form non-amyloid inclusions in the affected nervous tissues, but the role of these proteinaceous aggregates in disease onset and progression is still uncertain. To address this question, we designed a variant of FUS, FUS 1-359, which is predominantly cytoplasmic, highly aggregate-prone, and lacks a region responsible for RNA recognition and binding. Expression of FUS 1-359 in neurons of transgenic mice, at a level lower than that of endogenous FUS, triggers FUSopathy associated with severe damage of motor neurons and their axons, neuroinflammatory reaction, and eventual loss of selective motor neuron populations. These pathological changes cause abrupt development of a severe motor phenotype at the age of 2.5-4.5 months and death of affected animals within several days of onset. The pattern of pathology in transgenic FUS 1-359 mice recapitulates several key features of human ALS with the dynamics of the disease progression compressed in line with shorter mouse lifespan. Our data indicate that neuronal FUS aggregation is sufficient to cause ALS-like phenotype in transgenic mice.

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Related in: MedlinePlus

Degeneration and loss of spinal motor neurons in symptomatic FUS-TG mice.A and B, representative images of cresyl fast violet-stained sections through ventral spinal cord of presymptomatic (presym.) and symptomatic (sym.) FUS-TG and wild type animals (A) and a bar chart showing mean ± S.E. of motor neuron (MN) number in the ventral horn of the spinal cord (B). Inset in A shows degenerative changes (shrinking, chromatolysis) in a surviving motor neuron. The number of animals analyzed for the group is shown at the bottom of each bar (***, p < 0.001, Mann-Whitney test). Scale bars: A (top panel), 100 μm; A (bottom panel), 30 μm.
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Figure 4: Degeneration and loss of spinal motor neurons in symptomatic FUS-TG mice.A and B, representative images of cresyl fast violet-stained sections through ventral spinal cord of presymptomatic (presym.) and symptomatic (sym.) FUS-TG and wild type animals (A) and a bar chart showing mean ± S.E. of motor neuron (MN) number in the ventral horn of the spinal cord (B). Inset in A shows degenerative changes (shrinking, chromatolysis) in a surviving motor neuron. The number of animals analyzed for the group is shown at the bottom of each bar (***, p < 0.001, Mann-Whitney test). Scale bars: A (top panel), 100 μm; A (bottom panel), 30 μm.

Mentions: Aggregation and deposition of FUS protein are accompanied by severe damage to neurons and their axons. At the symptomatic stage, FUS-TG mice lose approximately half of their spinal motor neurons, whereas the majority of remaining neurons appear shrunken and/or chromatolytic (Fig. 4, A and B). However, the most probable cause of rapidly developing muscle paralysis and muscle atrophy (Fig. 5, A and B) in FUS-TG mice is the disconnection of the motor neuron axons from the muscle endplates (Fig. 5C) because significant neuronal loss and damage of myelinated fibers in peripheral nerves can be observed only at the late, generalized stage of the disease (Fig. 5, D and E).


Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice.

Shelkovnikova TA, Peters OM, Deykin AV, Connor-Robson N, Robinson H, Ustyugov AA, Bachurin SO, Ermolkevich TG, Goldman IL, Sadchikova ER, Kovrazhkina EA, Skvortsova VI, Ling SC, Da Cruz S, Parone PA, Buchman VL, Ninkina NN - J. Biol. Chem. (2013)

Degeneration and loss of spinal motor neurons in symptomatic FUS-TG mice.A and B, representative images of cresyl fast violet-stained sections through ventral spinal cord of presymptomatic (presym.) and symptomatic (sym.) FUS-TG and wild type animals (A) and a bar chart showing mean ± S.E. of motor neuron (MN) number in the ventral horn of the spinal cord (B). Inset in A shows degenerative changes (shrinking, chromatolysis) in a surviving motor neuron. The number of animals analyzed for the group is shown at the bottom of each bar (***, p < 0.001, Mann-Whitney test). Scale bars: A (top panel), 100 μm; A (bottom panel), 30 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757190&req=5

Figure 4: Degeneration and loss of spinal motor neurons in symptomatic FUS-TG mice.A and B, representative images of cresyl fast violet-stained sections through ventral spinal cord of presymptomatic (presym.) and symptomatic (sym.) FUS-TG and wild type animals (A) and a bar chart showing mean ± S.E. of motor neuron (MN) number in the ventral horn of the spinal cord (B). Inset in A shows degenerative changes (shrinking, chromatolysis) in a surviving motor neuron. The number of animals analyzed for the group is shown at the bottom of each bar (***, p < 0.001, Mann-Whitney test). Scale bars: A (top panel), 100 μm; A (bottom panel), 30 μm.
Mentions: Aggregation and deposition of FUS protein are accompanied by severe damage to neurons and their axons. At the symptomatic stage, FUS-TG mice lose approximately half of their spinal motor neurons, whereas the majority of remaining neurons appear shrunken and/or chromatolytic (Fig. 4, A and B). However, the most probable cause of rapidly developing muscle paralysis and muscle atrophy (Fig. 5, A and B) in FUS-TG mice is the disconnection of the motor neuron axons from the muscle endplates (Fig. 5C) because significant neuronal loss and damage of myelinated fibers in peripheral nerves can be observed only at the late, generalized stage of the disease (Fig. 5, D and E).

Bottom Line: Dysfunction of two structurally and functionally related proteins, FUS and TAR DNA-binding protein of 43 kDa (TDP-43), implicated in crucial steps of cellular RNA metabolism can cause amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases.To address this question, we designed a variant of FUS, FUS 1-359, which is predominantly cytoplasmic, highly aggregate-prone, and lacks a region responsible for RNA recognition and binding.These pathological changes cause abrupt development of a severe motor phenotype at the age of 2.5-4.5 months and death of affected animals within several days of onset.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, Cardiff University, Cardiff, Wales, United Kingdom.

ABSTRACT
Dysfunction of two structurally and functionally related proteins, FUS and TAR DNA-binding protein of 43 kDa (TDP-43), implicated in crucial steps of cellular RNA metabolism can cause amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases. The proteins are intrinsically aggregate-prone and form non-amyloid inclusions in the affected nervous tissues, but the role of these proteinaceous aggregates in disease onset and progression is still uncertain. To address this question, we designed a variant of FUS, FUS 1-359, which is predominantly cytoplasmic, highly aggregate-prone, and lacks a region responsible for RNA recognition and binding. Expression of FUS 1-359 in neurons of transgenic mice, at a level lower than that of endogenous FUS, triggers FUSopathy associated with severe damage of motor neurons and their axons, neuroinflammatory reaction, and eventual loss of selective motor neuron populations. These pathological changes cause abrupt development of a severe motor phenotype at the age of 2.5-4.5 months and death of affected animals within several days of onset. The pattern of pathology in transgenic FUS 1-359 mice recapitulates several key features of human ALS with the dynamics of the disease progression compressed in line with shorter mouse lifespan. Our data indicate that neuronal FUS aggregation is sufficient to cause ALS-like phenotype in transgenic mice.

Show MeSH
Related in: MedlinePlus