Distal axonopathy in an alsin-deficient mouse model

Deng, Han Xiang; Zhai, Hong; Fu, Rui; Shi, Yong; Gorrie, George; Yang, Yi; Liu, Erdong; Canto, Mauro C. Dal; Mugnaini, Enrico; Siddique, Teepu

doi:10.1093/hmg/ddm251

Cited by 44 publications

(36 citation statements)

References 42 publications

(73 reference statements)

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“…It is also worth noting that mouse motor neurons may be more resistant to the same pathogenic assaults affecting human motor neurons. For example, mice completely deficient of alsin did not develop an apparent motor neuron phenotype (17); in transgenic mice overexpressing SOD1 G93A , it appears that the mutant protein needs to reach a high enough threshold, which is at least three times that of mouse endogenous sod1 for the disease phenotype to develop (18). The expression level of our mutant ubiquilin2 in transgenic mice was similar to that of mouse endogenous ubqln2.…”

Section: Discussionmentioning

confidence: 68%

Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

Gorrie¹,

Fecto²,

Radzicki

et al. 2014

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

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Mutations in the gene encoding ubiquilin2 (UBQLN2) cause amyotrophic lateral sclerosis (ALS), frontotemporal type of dementia, or both. However, the molecular mechanisms are unknown. Here, we show that ALS/dementia-linked UBQLN2 P497H transgenic mice develop neuronal pathology with ubiquilin2/ubiquitin/p62-positive inclusions in the brain, especially in the hippocampus, recapitulating several key pathological features of dementia observed in human patients with UBQLN2 mutations. A major feature of the ubiquilin2-related pathology in these mice, and reminiscent of human disease, is a dendritic spinopathy with protein aggregation in the dendritic spines and an associated decrease in dendritic spine density and synaptic dysfunction. Finally, we show that the protein inclusions in the dendritic spines are composed of several components of the proteasome machinery, including Ub G76V -GFP, a representative ubiquitinated protein substrate that is accumulated in the transgenic mice. Our data, therefore, directly link impaired protein degradation to inclusion formation that is associated with synaptic dysfunction and cognitive deficits. These data imply a convergent molecular pathway involving synaptic protein recycling that may also be involved in other neurodegenerative disorders, with implications for development of widely applicable rational therapeutics.P rotein aggregates or inclusions with immunoreactivity to ubiquitin represent a common pathological hallmark in a broad range of late-onset neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) (1). However, the molecular mechanisms underlying the formation of these inclusions and their relationship to neuronal dysfunction and degeneration are poorly understood. Mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin2 (UBQLN2), have been recently shown to cause a subset of ALS, FTD-type of dementia, or both (2, 3). Notably, mutations within and in close proximity to the PXX domain of ubiquilin2 appear to have high penetrance as shown in familial cases (2). The distribution of ubiquilin2-positive inclusions in the brain and spinal cord is well correlated with cognitive and motor symptoms of patients with diverse etiology, including chromosome 9 open reading frame 72 (C9ORF72)-linked cases (2, 4). The ubiquilin2-positive inclusions appear to cover a wide range of protein inclusions, including those without TAR DNA binding protein (TDP43) immunoreactivity (2, 4), suggesting a primary role for ubiquilin2 in inclusion formation and neurodegeneration. Therefore, understanding the pathophysiological basis of UBQLN2-linked dementia may provide mechanistic insight into the pathogenesis of neurodegenerative disorders and allow for the design of rational therapies. To this end, we developed and characterized mutant UBQLN2 transgenic mice. ResultsDevelopment of UBQLN2 P497H Transgenic Mice. Human UBQLN2 is an intronless gene. We analyzed the UBQLN2 promoter ...

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Section: Discussionmentioning

confidence: 68%

Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

Gorrie¹,

Fecto²,

Radzicki

et al. 2014

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

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“…Lack of Alsin resulting from loss of function mutations of the ALS2 gene results in severe disorder of human corticospinal and corticobulbar tract degeneration with primary lateral sclerosis. However, in mouse models, Alsin deletion has minimal effect on ambulation and muscle tone ( 8,9 ).…”

Section: Resultsmentioning

confidence: 99%

Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis

Schüle

Siddique

Deng

et al. 2010

Journal of Lipid Research

102

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“…Axo-terminal degeneration of motor neurons also occurs in mice with mutations in the p150 Glued subunit of dynactin, although it is unclear whether axonopathy arises from impaired retrograde transport or an alteration in protein degradation [40,41]. The juvenile ALSassociated gene ALS2, encoding the protein Alsin, seems to play a role in transport and axonal maintenance, as several lines of Alsin-deficient mice show variable defects in endosomal trafficking of growth factor and neurotrophin receptors, including epidermal growth factor (EGF), insulin-like growth factor (IGF), and BDNF receptors [46,47], and some lines of Alsindeficient mice also show axonal degeneration of motor neurons [48,49]. The pathology of these diseases suggests that retrograde transport may play a special role in maintaining axonal health.…”

Section: Retrograde Transport and Neurodegenerationmentioning

confidence: 99%

Action in the axon: generation and transport of signaling endosomes

Cosker

Courchesne

Segal

2008

Current Opinion in Neurobiology

137

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Neurons extend axonal processes over long distances, necessitating efficient transport mechanisms to convey target-derived neurotrophic survival signals from remote distal axons to cell bodies. Retrograde transport, powered by dynein motors, supplies cell bodies with survival signals in the form of "signaling endosomes". In this review, we will discuss new advances in our understanding of the motor proteins that bind to and move signaling components in a retrograde direction, and discuss mechanisms that might specify distinct neuronal responses to spatially restricted neurotrophin signals. Disruption of retrograde transport leads to a variety of neurodegenerative diseases, highlighting the role of retrograde transport of signaling endosomes for axonal maintenance and the importance of efficient transport for neuronal survival and function. Retrograde axonal transport mechanismsNeurons extend long axons to contact post-synaptic targets far removed from the neuronal cell body. Hence long-range communication between the nerve ending and the cell body is essential for axonal pathfinding, target innervation, plasticity and survival. The neurotrophin family, including nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin 3 or 4 (NT-3 and NT-4), are well-characterized growth factors that are often produced in post-synaptic cells and initiate signals at axon terminals by binding specific Trk receptors [1,2]. How are these signals conveyed to the cell body in order to alter gene expression? Several lines of experiments indicate that transport by microtubule-dependent dynein motors transmit these long-range signals [3][4][5][6]. Although there exist alternative models [4,7,8], it is widely accepted that vesicular-based transport of a "signaling endosome" is required for many, if not most, aspects of retrograde signaling mechanisms and will be the focus of this review.In compartmentalized cultures of sensory and sympathetic neurons, activated phosphorylated Trks (P-Trks) accumulate in cell bodies upon distal axon exposure to neurotrophins [9][10][11]. The signaling endosome model proposes that upon ligand binding and activation, Trk receptors at the distal axon are internalized via clathrin-mediated [12][13][14] or pincher-dependent endocytosis [15,16]. The resultant vesicles containing the ligand-receptor complex are retrogradely transported to the cell body in order to mediate a survival response [3,[7][8][9][10][11]17, 18]. © 2008 Elsevier Ltd. All rights reserved.Corresponding author: Rosalind Segal (E-mail: rosalind_segal@dfci.harvard.edu), Phone (617) 632-4737; Fax (617) 632-2085. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered ...

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Distal axonopathy in an alsin-deficient mouse model

Cited by 44 publications

References 42 publications

Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis

Action in the axon: generation and transport of signaling endosomes

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