Glial Cell Dysfunction in C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Since the discovery of the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested—(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either C9orf72 repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in the disease progression. Dysregulation of the immune system, particularly glial cell dysfunction (mainly microglia and astrocytes), is demonstrated to play a pivotal role in both loss and gain of function theories of C9orf72 pathogenesis. In this review, we discuss the pathogenic roles of glial cells in C9orf72 ALS/FTD as evidenced by pre-clinical and clinical studies showing the presence of gliosis in C9orf72 ALS/FTD, pathologic hallmarks in glial cells, including TAR DNA-binding protein 43 (TDP-43) and p62 aggregates, and toxicity of C9orf72 glial cells. A better understanding of these pathways can provide new insights into the development of therapies targeting glial cell abnormalities in C9orf72 ALS/FTD.

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Modeling C9orf72-Related Frontotemporal Dementia and Amyotrophic Lateral Sclerosis in Drosophila

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.770937 ◽

2021 ◽

Vol 15 ◽

Author(s):

Joanne L. Sharpe ◽

Nikki S. Harper ◽

Duncan R. Garner ◽

Ryan J. H. West

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Loss Of Function ◽

Gain Of Function ◽

Dipeptide Repeat Proteins ◽

Repeat Proteins ◽

Individual Contributions ◽

The Individual ◽

Lateral Sclerosis ◽

Dipeptide Repeat

An intronic hexanucleotide (GGGGCC) expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In the decade following its discovery, much progress has been made in enhancing our understanding of how it precipitates disease. Both loss of function caused by reduced C9orf72 transcript levels, and gain of function mechanisms, triggered by the production of repetitive sense and antisense RNA and dipeptide repeat proteins, are thought to contribute to the toxicity. Drosophila models, with their unrivaled genetic tractability and short lifespan, have played a key role in developing our understanding of C9orf72-related FTD/ALS. There is no C9orf72 homolog in fly, and although this precludes investigations into loss of function toxicity, it is useful for elucidating mechanisms underpinning gain of function toxicity. To date there are a range of Drosophila C9orf72 models, encompassing different aspects of gain of function toxicity. In addition to pure repeat transgenes, which produce both repeat RNA and dipeptide repeat proteins (DPRs), RNA only models and DPR models have been generated to unpick the individual contributions of RNA and each dipeptide repeat protein to C9orf72 toxicity. In this review, we discuss how Drosophila models have shaped our understanding of C9orf72 gain of function toxicity, and address opportunities to utilize these models for further research.

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Far beyond the motor neuron: the role of glial cells in amyotrophic lateral sclerosis

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20160117 ◽

2016 ◽

Vol 74 (10) ◽

pp. 849-854

Author(s):

Paulo Victor Sgobbi de Souza ◽

Wladimir Bocca Vieira de Rezende Pinto ◽

Flávio Moura Rezende Filho ◽

Acary Souza Bulle Oliveira

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Glial Cell ◽

Glial Cells ◽

Motor Neurons ◽

Cell Interaction ◽

Cell Functions ◽

Glial Cell Interactions ◽

Lateral Sclerosis

ABSTRACT Motor neuron disease is one of the major groups of neurodegenerative diseases, mainly represented by amyotrophic lateral sclerosis. Despite wide genetic and biochemical data regarding its pathophysiological mechanisms, motor neuron disease develops under a complex network of mechanisms not restricted to the unique functions of the alpha motor neurons but which actually involve diverse functions of glial cell interaction. This review aims to expose some of the leading roles of glial cells in the physiological mechanisms of neuron-glial cell interactions and the mechanisms related to motor neuron survival linked to glial cell functions.

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Novel Optineurin Frameshift Insertion in a Family With Frontotemporal Dementia and Parkinsonism Without Amyotrophic Lateral Sclerosis

Frontiers in Neurology ◽

10.3389/fneur.2021.645913 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jacqueline Dominguez ◽

Jeryl Tan Yu ◽

Yi Jayne Tan ◽

Arlene Ng ◽

Ma Fe De Guzman ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Positive Family History ◽

Clinical Manifestations ◽

The Philippines ◽

Chromosome 9 ◽

Genetic Modifiers ◽

Reading Frame ◽

Hexanucleotide Repeat ◽

Lateral Sclerosis

Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene (MAPT), granulin precursor (GRN), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin (OPTN) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with four members harboring a novel frameshift insertion at OPTN (Chr 10:13166090 G>GA) p.Lys328GluTer11, three of whom presented with FTD-related phenotypes. Additionally, one sibling heterozygous for the frameshift insertion had a predominantly parkinsonian phenotype resembling corticobasal syndrome, but it remains to be determined if this phenotype is related to the frameshift insertion. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity.

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Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2017-316820 ◽

2017 ◽

Vol 89 (2) ◽

pp. 162-168 ◽

Cited By ~ 23

Author(s):

Oriol Dols-Icardo ◽

Alberto García-Redondo ◽

Ricardo Rojas-García ◽

Daniel Borrego-Hernández ◽

Ignacio Illán-Gala ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Pathogenic Mutation ◽

Genetic Alterations ◽

Repeat Expansion ◽

Chromosome 9 ◽

Systematic Screening ◽

Expansion Mutation ◽

Genetic Burden ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum.ObjectivesThe purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases.MethodsFrom an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes.ResultsWe identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4.ConclusionOur results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease.

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Properties of Glial Cell at the Neuromuscular Junction are Incompatible with synaptic repair in the SOD1G37R ALS mouse model

10.1101/2020.06.05.136226 ◽

2020 ◽

Author(s):

Martineau Éric ◽

Danielle Arbour ◽

Joanne Vallée ◽

Robitaille Richard

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neuromuscular Junction ◽

Motor Unit ◽

Glial Cell ◽

Glial Cells ◽

Motor Neurons ◽

Nerve Terminal ◽

Dependent Manner ◽

Repair Mechanisms ◽

Lateral Sclerosis

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motoneurons in a motor-unit (MU) dependent manner. Glial dysfunction contributes to numerous aspects of the disease. At the neuromuscular junction (NMJ), early alterations in perisynaptic Schwann cell (PSC), glial cells at this synapse, may impact their ability to regulate NMJ stability and repair. Indeed, muscarinic receptors (mAChR) regulate the repair phenotype of PSCs and are overactivated at disease-resistant NMJs (Soleus muscle) in SOD1G37R mice. However, it remains unknown whether this is the case at disease-vulnerable NMJs and whether it translates into an impairment of PSC-dependent repair mechanisms. We used Soleus and Sternomastoid muscles from SOD1G37R mice and performed Ca2+-imaging to monitor PSC activity and used immunohistochemistry to analyze their repair and phagocytic properties. We show that PSC mAChR-dependent activity was transiently increased at disease-vulnerable NMJs (Sternomastoid muscle). Furthermore, PSCs from both muscles extended disorganized processes from denervated NMJs and failed to initiate or guide nerve terminal sprouts at disease-vulnerable NMJs, a phenomenon essential for compensatory reinnervation. This was accompanied by a failure of numerous PSCs to upregulate Galectin-3 (MAC-2), a marker of glial axonal debris phagocytosis, upon NMJ denervation in SOD1 mice. Finally, differences in these PSC-dependent NMJ repair mechanisms were MU-type dependent, thus reflecting MU vulnerability in ALS. Together, these results reveal that neuron-glia communication is ubiquitously altered at the NMJ in ALS. This appears to prevent PSCs from adopting a repair phenotype, resulting in a maladapted response to denervation at the NMJ in ALS.SIGNIFICANCE STATEMENTUnderstanding how the complex interplay between neurons and glial cells ultimately lead to the degeneration of motor neurons and loss of motor function is a fundamental question to comprehend amyotrophic lateral sclerosis. An early and persistent alteration of glial cell activity takes place at the neuromuscular junction (NMJ), the output of motor neurons, but its impact on NMJ repair remains unknown. Here, we reveal that glial cells at disease-vulnerable NMJs often fail to guide compensatory nerve terminal sprouts and to adopt a phagocytic phenotype on denervated NMJs in SOD1G37R mice. These results show that glial cells at the NMJ elaborate an inappropriate response to NMJ degeneration in a manner that reflects motor-unit vulnerability and potentially impairs compensatory reinnervation.

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Gel-like inclusions of C-terminal fragments of TDP-43 sequester and inhibit proteasomes in neurons

10.1101/2021.03.15.435268 ◽

2021 ◽

Author(s):

Henrick Riemenschneider ◽

Qiang Guo ◽

Jakob Bader ◽

Frederic Frottin ◽

Daniel Farny ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Electron Tomography ◽

Biophysical Properties ◽

Gain Of Function ◽

Functional Assays ◽

Pathogenic Mutations ◽

Cryo Electron Tomography ◽

Substrate Processing ◽

Lateral Sclerosis

TDP-43 inclusions enriched in C-terminal fragments of ~25kDa ("TDP-25") are associated with neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we analyzed gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics and functional assays. TDP-25 inclusions are amorphous with gel-like biophysical properties and sequester proteasomes adopting exclusively substrate-processing conformations. This leads to proteostasis impairment, further enhanced by pathogenic mutations. These findings bolster the importance of proteasome dysfunction in ALS/FTD.

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Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-324647 ◽

2020 ◽

pp. jnnp-2020-324647

Author(s):

Virgilio Kmetzsch ◽

Vincent Anquetil ◽

Dario Saracino ◽

Daisy Rinaldi ◽

Agnès Camuzat ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Chromosome 9 ◽

Differentially Expressed ◽

Reading Frame ◽

Expression Levels ◽

Clinical Onset ◽

Plasma Microrna ◽

A Prospective Study ◽

Lateral Sclerosis

ObjectiveTo identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (C9orf72)-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in C9orf72 patients and presymptomatic carriers.MethodsThe PREV-DEMALS study is a prospective study including 22 C9orf72 patients, 45 presymptomatic C9orf72 mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers.ResultsFour miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with C9orf72 mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of C9orf72-associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients.ConclusionsWe identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset.Trial registration numberNCT02590276.

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Haploinsufficiency of TANK-binding kinase 1 prepones age-associated neuroinflammatory changes without causing motor neuron degeneration in aged mice

Brain Communications ◽

10.1093/braincomms/fcaa133 ◽

2020 ◽

Vol 2 (2) ◽

Cited By ~ 1

Author(s):

Clara Bruno ◽

Kirsten Sieverding ◽

Axel Freischmidt ◽

Takashi Satoh ◽

Paul Walther ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Gene Expression Pattern ◽

Incomplete Penetrance ◽

Immune Gene ◽

Loss Of Function ◽

Wild Type ◽

Age Dependent ◽

Old Mice ◽

Lateral Sclerosis

Abstract Loss-of-function mutations in TANK-binding kinase 1 cause genetic amyotrophic lateral sclerosis and frontotemporal dementia. Consistent with incomplete penetrance in humans, haploinsufficiency of TANK-binding kinase 1 did not cause motor symptoms in mice up to 7 months of age in a previous study. Ageing is the strongest risk factor for neurodegenerative diseases. Hypothesizing that age-dependent processes together with haploinsufficiency of TANK-binding kinase 1 could create a double hit situation that may trigger neurodegeneration, we examined mice with hemizygous deletion of Tbk1 (Tbk1+/− mice) and wild-type siblings up to 22 months. Compared to 4-month old mice, aged, 22-month old mice showed glial activation, deposition of motoneuronal p62 aggregates, muscular denervation and profound transcriptomic alterations in a set of 800 immune-related genes upon ageing. However, we did not observe differences regarding these measures between aged Tbk1+/− and wild-type siblings. High age did also not precipitate TAR DNA-binding protein 43 aggregation, neurodegeneration or a neurological phenotype in Tbk1+/− mice. In young Tbk1+/− mice, however, we found the CNS immune gene expression pattern shifted towards the age-dependent immune system dysregulation observed in old mice. Conclusively, ageing is not sufficient to precipitate an amyotrophic lateral sclerosis or frontotemporal dementia phenotype or spinal or cortical neurodegeneration in a model of Tbk1 haploinsufficiency. We hypothesize that the consequences of Tbk1 haploinsufficiency may be highly context-dependent and require a specific synergistic stress stimulus to be uncovered.

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The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

Cells ◽

10.3390/cells10081865 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1865

Author(s):

Nica Borgese ◽

Nicola Iacomino ◽

Sara Francesca Colombo ◽

Francesca Navone

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Adaptor Proteins ◽

Loss Of Function ◽

Membrane Contact Sites ◽

Physiological Processes ◽

Main Driver ◽

Single Allele ◽

Induced Pluripotent ◽

Lateral Sclerosis

The VAP proteins are integral adaptor proteins of the endoplasmic reticulum (ER) membrane that recruit a myriad of interacting partners to the ER surface. Through these interactions, the VAPs mediate a large number of processes, notably the generation of membrane contact sites between the ER and essentially all other cellular membranes. In 2004, it was discovered that a mutation (p.P56S) in the VAPB paralogue causes a rare form of dominantly inherited familial amyotrophic lateral sclerosis (ALS8). The mutant protein is aggregation-prone, non-functional and unstable, and its expression from a single allele appears to be insufficient to support toxic gain-of-function effects within motor neurons. Instead, loss-of-function of the single wild-type allele is required for pathological effects, and VAPB haploinsufficiency may be the main driver of the disease. In this article, we review the studies on the effects of VAPB deficit in cellular and animal models. Several basic cell physiological processes are affected by downregulation or complete depletion of VAPB, impinging on phosphoinositide homeostasis, Ca2+ signalling, ion transport, neurite extension, and ER stress. In the future, the distinction between the roles of the two VAP paralogues (A and B), as well as studies on motor neurons generated from induced pluripotent stem cells (iPSC) of ALS8 patients will further elucidate the pathogenic basis of p.P56S familial ALS, as well as of other more common forms of the disease.

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“My World Has Expanded Even Though I'm Stuck at Home”: Experiences of Individuals With Amyotrophic Lateral Sclerosis Who Use Augmentative and Alternative Communication and Social Media

American Journal of Speech-Language Pathology ◽

10.1044/2015_ajslp-15-0010 ◽

2015 ◽

Vol 24 (4) ◽

pp. 680-695 ◽

Cited By ~ 22

Author(s):

Jessica Caron ◽

Janice Light

Keyword(s):

Social Media ◽

Amyotrophic Lateral Sclerosis ◽

Augmentative And Alternative Communication ◽

Future Research ◽

Loss Of Function ◽

Alternative Communication ◽

Communication Modes ◽

Communication Needs ◽

Use Of Social Media ◽

Lateral Sclerosis

PurposeThis study aimed to expand the current understanding of how persons with amyotrophic lateral sclerosis (pALS) use augmentative and alternative communication and social media to address their communication needs.MethodAn online focus group was used to investigate the experiences of 9 pALS who use augmentative and alternative communication and social media. Questions posed to the group related to (a) current use of social media, (b) advantages of social media, (c) barriers to independent use, (d) supports to independent use, and (e) recommendations for developers, policy makers, and other pALS.ResultsParticipants primarily reported that use of social media was a beneficial tool that provided increased communication opportunities, connections to communication partners, and networks of support. Specific results are discussed with reference to the research as well as implications for practice and recommendations for future research.ConclusionsAs individuals with ALS experience loss of function, some communication modes may no longer be viable. Providing access to different modes of communication, including social media, can allow independence, participation and better quality of life.

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