Familial ALS with FUS P525L mutation: two Japanese sisters with multiple systems involvement

Mochizuki, Yoko; Isozaki, Eiji; Takao, Masaki; Hashimoto, Tokitada; Shibuya, Makoto; Arai, Makoto; Hosokawa, Masato; Kawata, Akihito; Oyanagi, Kiyomitsu; Mihara, Ban; Mizutani, Toshio

doi:10.1016/j.jns.2012.08.016

Cited by 33 publications

(37 citation statements)

References 27 publications

(69 reference statements)

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“…35 Greater degrees of basal ganglia degeneration in ALS have been associated with other ALS genotypes such as the FUS (fused in sarcoma) P525L mutation. 36 The finding of asymmetric structural changes is consistent with the typical asymmetric clinical presentation of ALS, and reflects previously reported imaging findings. The asymmetry is likely to be a function both of the sample sizes of the study groups and of disease duration.…”

Section: Resultssupporting

confidence: 90%

Basal ganglia involvement in amyotrophic lateral sclerosis

et al. 2013

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ALS is associated with widespread basal ganglia involvement. Caudate nucleus, hippocampus, and nucleus accumbens atrophy are key features of ALS. Dysfunction of frontostriatal networks is likely to contribute to the unique neuropsychological profile of ALS, dominated by executive dysfunction, apathy, and deficits in social cognition. Our quantitative imaging findings are consistent with postmortem studies and indicate that subcortical gray matter structures should be included in future biomarker studies of ALS.

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Section: Resultssupporting

confidence: 90%

Basal ganglia involvement in amyotrophic lateral sclerosis

et al. 2013

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“…Nearly all display an autosomal dominant pattern of inheritance, albeit with varying degrees of penetrance. Notably, some mutations such as P525L are associated with a more severe disease progression [31] and juvenile onset [8, 48], with apparently sporadic occurrence, presumably because the condition is frequently lethal before it can be transmitted [35]. …”

Section: Introductionmentioning

confidence: 99%

“…As in previous over-expression models [31, 47], they demonstrated that overexpression of WT FUS alone was sufficient to induce neurodegeneration, but that mutant FUS is more stable and pathogenic than WT. Pathogenicity in these models was mutation dependent, with FUS P525L mice showing motor neuron specific degeneration at a younger age and a greater degree of cytoplasmic FUS mislocalization than in the FUS R521C model, reflecting the mutation-dependent phenotype of human cases bearing these mutations [8, 48]. As in the previous Cre-LoxP model [70] there was also significant denervation of NMJ in both mutant models preceding neurodegeneration, adding weight to the suggestion that neuronal loss is a downstream consequence of NMJ denervation caused by these mutations.…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of FUS-associated ALS and FTD: insights from rodent models

Nolan

Talbot

Ansorge

2016

acta neuropathol commun

103

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Disruptions to genes linked to RNA processing and homeostasis are implicated in the pathogenesis of two pathologically related but clinically heterogeneous neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in the Fused-in-Sarcoma (FUS) gene encoding a 526 amino-acid RNA-binding protein are found in a small subset of ALS cases, but FUS mutations do not appear to be a direct cause of FTD. Structural and functional similarities between FUS and another ALS-related RNA-binding protein, TDP-43, highlight the potential importance of aberrant RNA processing in ALS/FTD, and this pathway is now a major focus of interest. Recently, several research groups have reported transgenic vertebrate models of FUSopathy, with varying results. Here, we discuss the evidence for FUS pathogenicity in ALS/FTD, review the experimental approaches used and phenotypic features of FUS rodent models reported to date, and outline their contribution to our understanding of pathogenic mechanisms. Further refinement of vertebrate models will likely aid our understanding of the role of FUS in both diseases.

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“…Patients with ALS experience a progressive loss of motor neurons in the spinal cord and brain stem, and may become completely paralyzed toward the later stages of the disease (Gordon, 2013). ALS was traditionally considered to be a pure motor disorder (van der Graaff et al, 2009), but is now considered to be a multisystem neurodegenerative disease including frontal lobe, basal ganglia, and substantia nigra, and the cerebellum (Cellura, 2011; Mochizuki et al, 2012; Williams, 2013). The involvement of the cerebellum in ALS was recently reviewed by Prell and Grosskreutz (2013).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Human SOD1 Leads to Discrete Defects in the Cerebellar Architecture in the Mouse

et al. 2017

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The human superoxide dismutase 1 (SOD1) gene is responsible for neutralizing supercharged oxygen radicals within the cell. Mutation in SOD1 gene causes amyotrophic lateral sclerosis (ALS). Recent studies have shown involvement of the cerebellum in ALS, although the cerebellar contribution in SOD1 transgenic mice remains unclear. Using immunohistopathology, we investigated the Purkinje cell phenotype in the vermis of the SOD1 transgenic mice cerebellum. Calbindin 1 (Calb1) and three well-known zone and stripe markers, zebrin II, HSP25, and PLCβ4 have been used to explore possible alteration in zone and stripe. Here we show that Calb1 expression is significantly reduced in a subset of the Purkinje cells that is almost aligned with the cerebellar zones and stripes pattern. The Purkinje cells of SOD1 transgenic mice display a pattern of Calb1 down-regulation, which seems to proceed to Purkinje cell degeneration as the mice age. The onset of Calb1 down-regulation in Purkinje cells begins from the central zone and continues into the nodular zone, however it has not been observed in the anterior and posterior zones. In a subgroup of SOD1 transgenic mice in which gait unsteadiness was apparent, down-regulation of Calb1 is seen in a subset of PLCβ4+ Purkinje cells in the anterior zone. These observations suggest that the Calb1− subset of Purkinje cells in the anterior zone, which receives somatosensory input, causes unsteady gait. Our data suggest that human SOD1 overexpression leads to Calb1 down-regulation in the zone and strip pattern and raise the question of whether SOD1 overexpression leads to Purkinje cells degeneration.

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Familial ALS with FUS P525L mutation: two Japanese sisters with multiple systems involvement

Cited by 33 publications

References 27 publications

Basal ganglia involvement in amyotrophic lateral sclerosis

Basal ganglia involvement in amyotrophic lateral sclerosis

Pathogenesis of FUS-associated ALS and FTD: insights from rodent models

Overexpression of Human SOD1 Leads to Discrete Defects in the Cerebellar Architecture in the Mouse

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