Making Connections: Pathology and Genetics Link Amyotrophic Lateral Sclerosis with Frontotemporal Lobe Dementia

Fecto, Faisal; Siddique, Teepu

doi:10.1007/s12031-011-9637-9

Cited by 66 publications

(58 citation statements)

References 101 publications

(152 reference statements)

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“…We note that the motor neuron phenotype and pathology are not recapitulated in these mice. However, this does not appear to be unusual, because mutations in several genes, including C9ORF72, VCP, FUS, TDP43, or UBQLN2 can cause either ALS or FTD, or both, in human patients (16). It is also worth noting that mouse motor neurons may be more resistant to the same pathogenic assaults affecting human motor neurons.…”

Section: Discussionmentioning

confidence: 93%

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: 93%

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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“…5 In spite of the phenotypic heterogeneity found in ALS, ALS/ FTLD and PDB and related disorders such as IBMPFD and POAG, the discovery of mutations in overlapping candidate genes, such as VCP, UBQLN2, CHMP2B and OPTN, points to a common pathogenic mechanism affecting the formation and clearance of misfolded proteins. 2 We previously reported that the genotypes of protein disulphide isomerase (P4HB), a redox enzyme that reduces formation of aberrant disulphide bonds, were associated with survival time of FALS, 28 supporting the hypothesis that factors interfering with proteostasis may modify disease progression and can be considered as therapeutic targets for ALS. The investigation of p62/SQSTM1 mutations in multiple cohorts provides further support for their contribution to a significant predisposition to disease in ALS.…”

Section: Discussionmentioning

confidence: 92%

“…Indeed, mutations in several components of protein homeostasis, such as UBQLN2, charged multivesicular body protein 2B (CHMP2B), OPTN and valosin containing protein (VCP), are also present in less prevalent forms of ALS and ALS/FTD. 2 Interestingly, mutations in OPTN and VCP are also seen in other allelic forms characterised by TDP-43-positive polyubiquitinated inclusions, primary open angle glaucoma (POAG), and inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD), respectively.…”

Section: Introductionmentioning

confidence: 99%

Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB

2013

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Mutations in the SQSTM1 gene have been reported to be associated with amyotrophic lateral sclerosis (ALS). We sought to determine the frequency of these mutations in a UK familial ALS ( Pro392Leu) carriers were heterozygous for a previously reported founder haplotype for PDB, where this mutation has an established causal effect. The frequency of the p.(Pro392Leu) mutation in this UK FALS cohort was 2.3% and 0.97% overall including three previously screened FALS cohorts. Our results confirm the presence of the p.(Pro392Leu) SQSTM1 mutation in FALS. This mutation is the most common SQSTM1 mutation found in ALS to date, and a likely pathogenicity is supported by having an established causal role in PDB. The occurrence of the same mutation in ALS and PDB is indicative of a common pathogenic pathway that converges on protein homeostasis.

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“…Bu iki hastalık grubunda VBM ile serebellumda spesifik patternlerde subrejyonel atrofi tespit edilmiştir 33 . ALS ve FTD ayrımında MRI ve MRS teknikleri kullanılabilmekle birlikte kombine hastalıkta (ALS ve FTRD) kullanıldıklarında bu iki hastalığın tek bir patolojik sürece ait farklı özellikler gösterdikleri saptanmıştır 1,25,34 .…”

Section: Görüntülemeunclassified

“…Bu inflamasyonu azaltmak, büyüme faktörlerini artırmak ile mümkün olabilir 25 . Parkinson ve Alzheimer hastalığında olduğu gibi ALS'de de non-nöronal hücrelerin nöronal hücre kaybına katkıda bulunduğu düşünülmektedir 9,20 .…”

Section: Güncel Tedavi Yaklaşımlarıunclassified

Amyotrofik lateral skleroz: klinik özellikler ve güncel tedavi yaklaşımları

Koca¹

2015

Arşiv Kaynak Tarama Dergisi

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Amyotrophic lateral sclerosis also known as Lou Gehring's disease, is the most common motor neuron disease characterized by motor neuron degeneration in the primary cortex, brainstem and spinal cord. This leads to widespread paralysis, respiratory insufficiency and death within an average of 3-5 years from disease onset. Majority of cases is sporadic and only 10% have a family story. One of the most interesting discovery in the field of neurodegeneration in recent years is genetic mutation in the C9orf72 (chromosome 9 open reading frame 72) gene, the most common mutation found to be causative of frontotemporal dementia, amyotrophic lateral sclerosis and concomitant of these two diseases. Currently curative therapy for amyotrophic lateral sclerosis is lacking. To date, one medication, Riluzole, has been proved to prolong survival, approximately 3-5 months, in amyotrophic lateral sclerosis. Researches aim to slow disease progression by targeting known pathophysiological pathways or genetics defects. Only symptomatic care to improve quality of life and survival is suggested. These includes respiratory and nutrition support; dysphagia and gastrostomy management; communication and mobility programs; spasticity prevention; pain medication; management of cognitive dysfunction, depression, mood disorders (especially apathy), fatigue, sleep disturbance and prevention of deep venous thrombosis.

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Making Connections: Pathology and Genetics Link Amyotrophic Lateral Sclerosis with Frontotemporal Lobe Dementia

Cited by 66 publications

References 101 publications

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

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

Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB

Amyotrofik lateral skleroz: klinik özellikler ve güncel tedavi yaklaşımları

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