A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin

Lowe, James; Lennox, Graham; Jefferson, David; Morrell, Ken; McQuire, D.; Gray, Trevor; Landon, Michael; Doherty, Fergus J.; Mayer, R. John

doi:10.1016/0304-3940(88)90296-0

Cited by 214 publications

(95 citation statements)

References 12 publications

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“…6 and 7) disruption of the neurofilament network and an increase in ubiquitin and p62/ SQSTM levels in motor neurons (Fig. 6) similar to the human ALS pathology (12)(13)(14)(15)(16). These results establish a progressive disease model for ALS.…”

Section: Discussionsupporting

confidence: 55%

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: Discussionsupporting

confidence: 55%

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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“…These inclusions are immunoreactive to a number of specific antibodies, including to the neurofilament subunit proteins: low (NFL), intermediate (NFM), and high (NFH) molecular weight, ubiquitin, neuronal nitric oxide synthase (NOS type I), copper/zinc superoxide dismutase (SOD1), and nitrotyrosine [11][12][13][14]. Diffuse perikaryal ubiquitin immunoreactivity and skeins of immunoreactive material, independent of aggregates, have also been observed [15]. The observation of nitrotyrosine immunoreactivity of neurofilament aggregates might suggest that aberrant or excessive protein nitration, as a consequence of excessive oxidative metabolism, occurs in ALS.…”

Section: Neuropathological Featuresmentioning

confidence: 97%

Motor neuron disease and trace element toxicity

Strong

2000

J. Trace Elem. Exp. Med.

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“…In the meantime, the analysis of ubiquitination in the developing and mature brain has become a major new focus in neuroscience, not least because ubiquitination seems to play a key role in neurodegenerative disorders [16][17][18] . Thus, understanding the molecular mechanisms by which the different phases of nerve cell development and differentiation are coordinated by ubiquitination is of substantial importance for our understanding of normal brain development and function as well as of corresponding pathological perturbations.…”

Section: Ubiquitylation Is a Sequential Reaction Mediated By Three CLmentioning

confidence: 99%

The role of ubiquitylation in nerve cell development

2011

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| Nerve cell development in the brain is a tightly regulated process. The generation of neurons from precursor cells, their migration to the appropriate target sites, their extensive arborisation, and their integration into functional networks through synapse formation and refinement are governed by multiple interdependent signaling cascades. The function and turnover of proteins involved in these signaling cascades, in turn, are spatially and temporally controlled by ubiquitination. Recent advances have provided first insights into the highly complex and intricate molecular pathways that regulate ubiquitination during all stages of neural development and operate in parallel with other regulatory processes such as phosphorylation or cyclic nucleotide signaling.

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A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin

Cited by 214 publications

References 12 publications

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

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

Motor neuron disease and trace element toxicity

The role of ubiquitylation in nerve cell development

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