Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)

Lattante, Serena; Ciura, Sorana; Rouleau, Guy A.; Kabashi, Edor

doi:10.1016/j.tig.2015.03.005

Cited by 115 publications

(92 citation statements)

References 175 publications

(210 reference statements)

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“…Among the genes involved in the disease, mutations in Cu/Zn-superoxide dismutase 1 ( SOD1 ), fused-in-sarcoma ( FUS ), TARDBP , and C9ORF72 , hexanucleotide CCCCGG expansions are the most frequently found in familial and sporadic cases [1,2,6]. …”

Section: Introductionmentioning

confidence: 99%

ALS-Related Mutant FUS Protein Is Mislocalized to Cytoplasm and Is Recruited into Stress Granules of Fibroblasts from Asymptomatic FUS P525L Mutation Carriers

et al. 2017

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Background: Amyotrophic lateral sclerosis (ALS) shows a strong genetic basis, with SOD1, FUS, TARDBP, and C9ORF72 being the genes most frequently involved. This has allowed identification of asymptomatic mutation carriers, which may be of help in understanding the molecular changes preceding disease onset. Objectives: We studied the cellular expression of FUS protein and the effect of heat-shock- and dithiothreitol-induced stress in fibroblasts from FUS P525L mutation carriers, healthy controls, and patients with sporadic ALS. Methods: Western blots and immunocytochemistry were performed to study the subcellular localization of FUS protein. Control and stressed cells were double stained with FUS and the stress marker TIA-R. Results: Fibroblasts from healthy controls and sporadic ALS cases showed a prominent nuclear FUS expression. In the 2 FUS P525L mutation carriers, instead, most cells showed a protein localization in both nucleus and cytoplasm, or exclusively in the cytoplasm. Stress prompted the formation of cytoplasmic granules in all subjects and in sporadic ALS FUS mislocalization to the cytoplasm. Cytoplasmic FUS was recruited into stress granules, which showed a time-dependent decrease in all subjects. However, in the FUS P525L fibroblasts, the granules persisted longer, and they were more numerous than those detected in the cells from controls and sporadic ALS patients. Conclusions: We show that in fibroblasts of FUS P525L mutation carriers, FUS mislocalized to the cytoplasm where it redistributed into stress granules with likely a dose effect, i.e. a higher number of cells with granules, which persist longer, than in controls and ALS cases. These data represent an early molecular change occurring before ALS onset, suggesting a transient preaggregative state.

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Section: Introductionmentioning

confidence: 99%

ALS-Related Mutant FUS Protein Is Mislocalized to Cytoplasm and Is Recruited into Stress Granules of Fibroblasts from Asymptomatic FUS P525L Mutation Carriers

et al. 2017

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“…A number of ALS cases are dominantly inherited and more than 20 genes have been associated with ALS, in particular C9ORF72, TARDBP, FUS and SOD1 [44]. Most experimental research has involved expression of mutant SOD1 in transgenic mice, leading to development of typical ALS symptoms.…”

Section: Introductionmentioning

confidence: 99%

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

et al. 2016

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Abstract:Microglia are the resident phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to overall increased phagocytic activity and production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in monocytes and microglia are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT 2B ), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT 2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT 2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT 2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT 2B mRNA in spinal cord and displayed less pronounced degeneration of mononuclear phagocytes than patients carrying two copies of the more common A allele. Thus functional 5-HT 2B receptors limit degeneration of spinal cord macrophages (most likely microglia), and slow disease progression in ALS. Targeting this receptor might be therapeutically useful.

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“…Rab3 (Wada et al, 1997) 1 (Figueiredo et al, 2008) 2 Rab27 (Mahoney et al, 2006) 4 (Figueiredo et al, 2008) 2 (Yoshimura et al, 2010) 1 Rab3, Kif1a, Kif1b, DR4, DR5, TNFR1, JNK3, LRDD, IA-2 (Marat et al, 2011) Rabconnectin-3 (Kawabe et al, 2003) Madd-null mice (Tanaka et al, 2001) C. elegans aex-3 mutant (Iwasaki et al, 1997) DENN-related FLCN (201163) folliculin Rab35 (Nookala et al, 2012) 1 GAP for RagC/D GTPase (Tsun et al, 2013) Birt-Hogg-Dubé syndrome Flcn-, Fnip1-, Fnip2-null mice (Schmidt and Linehan, 2015) FNIP1 ( C9ORF72 (427370) DENNL72 ND Rab1, Rab5, Rab7, Rab11, ubiquilin-1/2, hnRNPA1, hnRNPA2/B1, actin (Farg, et al, 2014) C9orf72-null mice (Panda et al, 2013;Koppers et al, 2015) Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (Lattante et al, 2015) SMCR8 ( …”

Section: Denn and Denn-related Proteinsmentioning

confidence: 99%

Multiple Types of Guanine Nucleotide Exchange Factors (GEFs) for Rab Small GTPases

Ishida

Oguchi

Fukuda

2016

Cell Struct. Funct.

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ABSTRACT. Rab small GTPases are highly conserved master regulators of membrane traffic in all eukaryotes. The same as the activation and inactivation of other small GTPases, the activation and inactivation of Rabs are tightly controlled by specific GEFs (guanine nucleotide exchange factors) and GAPs (GTPase-activating proteins), respectively. Although almost all Rab-GAPs reported thus far have a TBC (Tre-2/Bub2/Cdc16)/Rab-GAP domain in common, recent accumulating evidence has indicated the existence of a number of structurally unrelated types of Rab-GEFs, including DENN proteins, VPS9 proteins, Sec2 proteins, TRAPP complexes, heterodimer GEFs (Mon1-Ccz1, HPS1-HPS4 (BLOC-3 complex), Ric1-Rgp1 and Rab3GAP1/2), and other GEFs (e.g., REI-1 and RPGR). In this review article we provide an up-to-date overview of the structures and functions of all putative Rab-GEFs in mammals, with a special focus on their substrate Rabs, interacting proteins, associations with genetic diseases, and intracellular localizations.

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Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)

Cited by 115 publications

References 175 publications

ALS-Related Mutant FUS Protein Is Mislocalized to Cytoplasm and Is Recruited into Stress Granules of Fibroblasts from Asymptomatic <b><i>FUS </i></b>P525L Mutation Carriers

ALS-Related Mutant FUS Protein Is Mislocalized to Cytoplasm and Is Recruited into Stress Granules of Fibroblasts from Asymptomatic <b><i>FUS </i></b>P525L Mutation Carriers

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

Multiple Types of Guanine Nucleotide Exchange Factors (GEFs) for Rab Small GTPases

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