Key role of UBQLN2 in pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia

ObjectiveTo investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers.MethodsThe neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA.ResultsCSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (−80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05).ConclusionOur data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome.

Download Full-text

The role of sequestosome 1/p62 protein in amyotrophic lateral sclerosis and frontotemporal dementia pathogenesis

Neural Regeneration Research ◽

10.4103/1673-5374.284977 ◽

2020 ◽

Vol 15 (12) ◽

pp. 2186

Author(s):

SarahLyn Rea ◽

AdrianaDelice Foster

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Sequestosome 1 ◽

Lateral Sclerosis

Download Full-text

The role of transactive response DNA-binding protein-43 in amyotrophic lateral sclerosis and frontotemporal dementia

Current Opinion in Neurology ◽

10.1097/wco.0b013e3283168d1d ◽

2008 ◽

Vol 21 (6) ◽

pp. 693-700 ◽

Cited By ~ 64

Author(s):

Ian RA Mackenzie ◽

Rosa Rademakers

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Dna Binding ◽

Frontotemporal Dementia ◽

Binding Protein ◽

Dna Binding Protein ◽

Lateral Sclerosis

Download Full-text

TDP-43 and Inflammation: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

International Journal of Molecular Sciences ◽

10.3390/ijms22157781 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7781

Author(s):

Fiona Bright ◽

Gabriella Chan ◽

Annika van Hummel ◽

Lars M. Ittner ◽

Yazi D. Ke

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Active Role ◽

Dna Binding Protein ◽

Ubiquitinated Protein ◽

Immune Mediated ◽

The Central Nervous System ◽

Specific Association ◽

Lateral Sclerosis

The abnormal mislocalisation and ubiquitinated protein aggregation of the TAR DNA binding protein 43 (TDP-43) within the cytoplasm of neurons and glia in the central nervous system (CNS) is a pathological hallmark of early-onset neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The pathomechanisms underlying abnormal mislocalisation and aggregation of TDP-43 remain unknown. However, there is a growing body of evidence implicating neuroinflammation and immune-mediated mechanisms in the pathogenesis of neurodegeneration. Importantly, most of the evidence for an active role of immunity and inflammation in the pathogenesis of ALS and FTD relates specifically to TDP-43, posing the question as to whether immune-mediated mechanisms could hold the key to understanding TDP-43’s underlying role in neurodegeneration in both diseases. Therefore, this review aims to piece together key lines of evidence for the specific association of TDP-43 with key immune and inflammatory pathways to explore the nature of this relationship and the implications for potential pathomechanisms underlying neurodegeneration in ALS and FTD.

Download Full-text

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

Acta Neuropathologica ◽

10.1007/s00401-020-02203-0 ◽

2020 ◽

Vol 140 (5) ◽

pp. 599-623

Author(s):

Alexander Bampton ◽

Lauren M. Gittings ◽

Pietro Fratta ◽

Tammaryn Lashley ◽

Ariana Gatt

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Rna Binding ◽

Rna Binding Proteins ◽

Comprehensive Overview ◽

Cryptic Exon ◽

Functional Roles ◽

Heterogeneous Nuclear Ribonucleoproteins ◽

Lateral Sclerosis

Abstract Dysregulated RNA metabolism is emerging as a crucially important mechanism underpinning the pathogenesis of frontotemporal dementia (FTD) and the clinically, genetically and pathologically overlapping disorder of amyotrophic lateral sclerosis (ALS). Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins with diverse, multi-functional roles across all aspects of mRNA processing. The role of these proteins in neurodegeneration is far from understood. Here, we review some of the unifying mechanisms by which hnRNPs have been directly or indirectly linked with FTD/ALS pathogenesis, including their incorporation into pathological inclusions and their best-known roles in pre-mRNA splicing regulation. We also discuss the broader functionalities of hnRNPs including their roles in cryptic exon repression, stress granule assembly and in co-ordinating the DNA damage response, which are all emerging pathogenic themes in both diseases. We then present an integrated model that depicts how a broad-ranging network of pathogenic events can arise from declining levels of functional hnRNPs that are inadequately compensated for by autoregulatory means. Finally, we provide a comprehensive overview of the most functionally relevant cellular roles, in the context of FTD/ALS pathogenesis, for hnRNPs A1-U.

Download Full-text

The C9ORF72 Gene, Implicated in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia, Encodes a Protein That Functions in Control of Endothelin and Glutamate Signaling

Molecular and Cellular Biology ◽

10.1128/mcb.00155-18 ◽

2018 ◽

Vol 38 (22) ◽

Cited By ~ 5

Author(s):

Vitalay Fomin ◽

Patricia Richard ◽

Mainul Hoque ◽

Cynthia Li ◽

Zhuoying Gu ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Morphological Changes ◽

Cell Models ◽

Glutamate Signaling ◽

Protein Levels ◽

Rna Analysis ◽

C9orf72 Gene ◽

Lateral Sclerosis

ABSTRACT A GGGGCC repeat expansion in the C9ORF72 (C9) gene is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Several mechanisms have been proposed to account for its toxicity, including the possibility that reduced C9 protein levels contribute to disease. To investigate this possibility, we examined the effects of reduced C9 levels in several cell systems. We first showed that C9 knockdown (KD) in U87 glioblastoma cells results in striking morphological changes, including vacuolization and alterations in cell size. Unexpectedly, RNA analysis revealed changes in expression of many genes, including genes involved in endothelin (EDN) signaling and immune system pathways and multiple glutamate cycling genes (e.g., EAAT2), which were verified in several cell models, including astrocytes and brain samples from C9-positive patients. Consistent with deregulation of the glutamate cycling genes, elevated intracellular glutamate was detected in both KD cells and patient astrocytes. Importantly, levels of mRNAs encoding EDN1 and its receptors, known to be elevated in ALS, were sharply increased by C9 KD, likely resulting from an observed activation of NF-κB signaling and/or a possible role of a C9 isoform in gene control.

Download Full-text