The phenotypic variability of amyotrophic lateral sclerosis

Swinnen, Bart; Robberecht, Wim

doi:10.1038/nrneurol.2014.184

Cited by 460 publications

(394 citation statements)

References 107 publications

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“…For example, mutant SOD1 toxicity has been shown in neurons outside of the primary motor system in the dorsal root ganglia, midbrain, and brainstem (28)(29)(30)(31). Likewise, neurodegeneration has been shown to occur in nonmotor neuron cell populations including DRG neurons in ALS patients, albeit the degeneration develops later than motor neurons during the disease progression (32). Thus, our observation that the motor neurons degenerate more rapidly than the DRG neurons in the PFN1 mutant mice (Fig.…”

Section: Discussionmentioning

confidence: 68%

Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity

Yang

Danielson

Qiao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the profilin 1 (PFN1) gene cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease caused by the loss of motor neurons leading to paralysis and eventually death. PFN1 is a small actin-binding protein that promotes formin-based actin polymerization and regulates numerous cellular functions, but how the mutations in PFN1 cause ALS is unclear. To investigate this problem, we have generated transgenic mice expressing either the ALSassociated mutant (C71G) or wild-type protein. Here, we report that mice expressing the mutant, but not the wild-type, protein had relentless progression of motor neuron loss with concomitant progressive muscle weakness ending in paralysis and death. Furthermore, mutant, but not wild-type, PFN1 forms insoluble aggregates, disrupts cytoskeletal structure, and elevates ubiquitin and p62/ SQSTM levels in motor neurons. Unexpectedly, the acceleration of motor neuron degeneration precedes the accumulation of mutant PFN1 aggregates. These results suggest that although mutant PFN1 aggregation may contribute to neurodegeneration, it does not trigger its onset. Importantly, these experiments establish a progressive disease model that can contribute toward identifying the mechanisms of ALS pathogenesis and the development of therapeutic treatments.A LS is a neurodegenerative disease that causes a relentless progressive loss of motor neurons, leading to progressive weakness that ends in paralysis and death (1). Mutations in the PFN1 gene have been identified as a genetic cause for ALS (2, 3). PFN1 is a major regulator of actin polymerization through its ability to bind actin-ADP monomers and promote the conversion of actin-ADP to actin-ATP, through transporting the actin-ATP monomers and through its interactions within formins present at the growing end of actin filaments. Additionally PFN1 binds to phosphoinositides and a large network of proteins with poly-Lproline stretches. Through these binding interactions, PFN1 regulates several cellular functions including actin dynamics, membrane trafficking, neuronal synaptic structure and activity, small GTPase signaling, and others (4). Despite our understanding of its function, how PFN1 mutations cause motor neuron degeneration remains elusive. Some evidence implicates a loss of function in the mutants. The ALS-associated mutations cause structural instability and accumulate in cells at lower levels than the wild-type protein (5). Mutant PFN1 binds less efficiently to actin than the wild-type protein, suggesting that the mutations compromise PFN1 function (3). The severest mutations also are incapable of compensating for loss-of-function PFN1 mutation in yeast (6). Other evidence supports a gain of function. Expression of mutant, but not wild-type, PFN1 inhibits filamentous actin formation and impairs growth cone function and neurite growth (3). Furthermore, PFN1 mutants have been shown to alter stress granule dynamics in cultured mammalian cells and form cellular aggregates that may contain other proteins contributing to path...

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Section: Discussionmentioning

confidence: 68%

Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity

Yang

Danielson

Qiao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Comparably, frontal lobe atrophy was described in two siblings with a homozygous FIG4 frameshift variant and Yunis-Varón syndrome, 10 whereby extramotor, in particular frontotemporal, affection occurs in the majority of fALS as well as sALS cases. 2,26,27 By clinical and electrophysiological assessment, we found that UMN predominance was significantly more frequent in patients with versus without FIG4 variants of our cohort. Similarly, very prominent corticospinal tract findings were previously reported in four of nine ALS patients carrying heterozygous FIG4 variants.…”

Section: Fig4 Variants In a Centralmentioning

confidence: 59%

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

et al. 2017

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We aimed to identify the genetic cause of the devastating neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a German family with two affected individuals, and to assess the prevalence of variants in the identified risk gene, FIG4, in a central European ALS cohort. Whole-exome sequencing (WES) and an overlapping data analysis strategy were performed in an ALS family with autosomal dominant inheritance and incomplete penetrance. Additionally, 200 central European ALS patients were analyzed using whole-exome or targeted sequencing. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization to explore genotype-phenotype relationships. WES analysis of the ALS family identified the rare heterozygous frameshift variant FIG4:c.759delG, p.(F254Sfs*8) predicted to delete the catalytic domain and active center from the encoded phosphoinositide 5-phosphatase with a key role in endosomal vesicle trafficking. Additionally, novel or rare heterozygous FIG4 missense variants predicted to be deleterious were detected in five sporadic ALS patients revealing an overall FIG4 variant frequency of 3% in our cohort. Four of six variants identified were previously associated with ALS or the motor and sensory neuropathy Charcot-Marie-Tooth disease type 4J (CMT4J), whereas two variants were novel. In FIG4 variant carriers, disease duration was longer and upper motor neuron predominance was significantly more frequent compared with ALS patients without FIG4 variants. Our study provides evidence for FIG4 as an ALS risk gene in a central European cohort, adds new variants to the mutational spectrum, links ALS to CMT4J on a genetic level, and describes a distinctive ALS phenotype for FIG4 variant carriers.

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“…Because the clinical presentation and progression rate are highly heterogeneous, 5 it remains challenging to identify the true biologic effects of drug testing in clinical trials. Exploring new processing methods and hypotheses would promote a greater understanding of the physiopathologic processes.…”

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confidence: 99%