Differential Involvement of Optineurin in Amyotrophic Lateral Sclerosis With or Without &lt;emph type="ital"&gt;SOD1&lt;/emph&gt; Mutations

Deng, Han Xiang

doi:10.1001/archneurol.2011.178

Cited by 62 publications

(41 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, about 5%-10% of ALS cases have a family history of the disorder, typically with dominant inheritance. During the past decades, pathogenic mutations in a number of genes, including ORF 72 on chromosome 9 (C9orf72), superoxide dismutase 1 (SOD1), TAR DNA binding protein (TARDBP, also known as TDP- 43), FUS RNA binding protein (FUS), heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), sequestosome 1 (SQSTM1), valosin-containing protein (VCP), optineurin (OPTN), TANK binding kinase 1 (TBK1), ubiquilin 2 (UBQLN2), and profilin 1 (PFN1), have been identified in ALS (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). These genes are involved in a variety of cellular pathways, including protein homeostasis, RNA metabolism, and cytoskeletal dynamics.…”

Section: Introductionmentioning

confidence: 99%

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Lall¹,

Baloh²

2017

Journal of Clinical Investigation

143

102

View full text Add to dashboard Cite

Genetic connections between microglia and neurodegenerationMicroglia are the main cells in the CNS responsible for immune surveillance and are critical for normal development and homeostasis (34)(35)(36). Under steady-state conditions, "ramified" microglia continuously survey the local microenvironment for any foreign antigens and insults. The resident microglia are Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a "dual effect" on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration.

show abstract

Section: Introductionmentioning

confidence: 99%

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Lall¹,

Baloh²

2017

Journal of Clinical Investigation

143

102

View full text Add to dashboard Cite

show abstract

“…OPTN is localized in cytoplasmic inclusions with ubiquitin and TDP-43 in ALS affected motor neurons (Hortobagyi et al, 2011). There are conflicting studies about OPTN co-localization with SOD1 and FUS (Deng et al, 2011a; Hortobagyi et al, 2011; Keller et al, 2012). OPTN inclusions are present in several other neurodegenerative diseases (Osawa et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

TDP-43/FUS in motor neuron disease: Complexity and challenges

Guerrero

Wang

Mitra

et al. 2016

Progress in Neurobiology

107

122

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.

show abstract

“…In SOD1-linked ALS, these inclusions are immunoreactive to ubiquitin, p62, and SOD1. Recent work has shown that TDP-43, FUS, and optineurin (OPTN) are components of pathological inclusions seen in SOD1-negative FALS, SALS, and ALS-FTD, but not in SOD1-linked ALS (Mackenzie et al 2007;Deng et al 2010Deng et al , 2011aHortobagyi et al 2011;Osawa et al 2011). We recently reported that UBQLN2-positive skein-like inclusions appear in all ALS cases including those with SOD1 mutations, indicating that UBQLN2 is a common component in the skein-like inclusions of a wide variety of ALS (Deng et al 2011b).…”

Section: Family 6885mentioning

confidence: 99%

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

Fecto

Siddique

2011

J Mol Neurosci

View full text Add to dashboard Cite

Over the last couple of decades, there has been a growing body of clinical, genetic, and histopathological evidence that similar pathological processes underlie amyotrophic lateral sclerosis (ALS) and some types of frontotemporal lobe dementia (FTD). Even though there is great diversity in the genetic causes of these disorders, there is a high degree of overlap in their histopathology. Genes linked to rare cases of familial ALS and/or FTD, like FUS, TARDBP, OPTN, and UBQLN2 may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of etiologically diverse forms of ALS and ALS-FTD. Additionally, there are major loci for ALS-FTD on chromosomes 9p and 15q. Identification of causative genetic alterations at those loci will be an important step in understanding the pathogenesis of juvenile- and adult-onset ALS and ALS-FTD. Interactions between TDP-43, FUS, optineurin, and ubiquilin 2 need to be studied to understand their common molecular pathways. Future efforts should also be directed towards generation and characterization of in vivo models to dissect the pathogenic mechanisms of these diseases. Such efforts will rapidly accelerate the discovery of new drugs that regulate accumulation of pathogenic proteins and their downstream consequences.

show abstract

Differential Involvement of Optineurin in Amyotrophic Lateral Sclerosis With or Without <emph type="ital">SOD1</emph> Mutations

Cited by 62 publications

References 31 publications

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

TDP-43/FUS in motor neuron disease: Complexity and challenges

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

Contact Info

Product

Resources

About