C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis

Rooney, James; Fogh, Isabella; Westeneng, Henk Jan; Vajda, Alice; McLaughlin, Russell L.; Heverin, Mark; Jones, Ashley; Eijk, Ruben van; Calvo, Andrea; Mazzini, Letizia; Morrison, Karen; Shaw, Pamela J.; Robberecht, Wim; Damme, Philip Van; Al‐Chalabi, Ammar; Berg, Leonard van den; Chiò, Adriano; Veldink, Jan H.; Hardiman, Orla

doi:10.1136/jnnp-2016-314093

Cited by 34 publications

(26 citation statements)

References 31 publications

(9 reference statements)

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“…For instance, disease phenotype is more penetrant and rapidly progressing in females in one transgenic line of C9orf72 mice (Liu et al, 2016). However, studies on C9orf72 patient cohorts report conflicting results, with women having either a better (Rooney et al, 2017;Trojsi et al, 2019) or a worse (Watanabe et al, 2015) survival time after onset. Likewise, the incidence of sporadic ALS, but not familial ALS, is higher in men than in women, but bulbar-onset ALS is more common in women and is associated with a poor prognosis (McCombe and Henderson, 2010;Kiernan et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Martineau

Polo

Velde

et al. 2020

eNeuro

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Progressive loss of neuromuscular junctions (NMJs) is an early event in amyotrophic lateral sclerosis (ALS), preceding the global degeneration of motor axons and being accompanied by new axonal sprouting within the same axonal arbor. Some aspects of ALS onset and progression seem to be affected by sex in animal models of the disease. However, whether there are sex-specific differences in the pattern or time course of NMJ loss and repair within single motor axons remains unknown. We performed further analysis of a previously published in vivo dataset, obtained from male and female SOD1 G37R mice. We found that NMJ losses are as frequent in male and female motor axons but, intriguingly, axonal sprouting is more frequent in female than male mice, resulting in a net increase of axonal arborization. Interestingly, these numerous new axonal branches in female mice are associated with a slightly faster decline in grip strength, increased NMJ denervation, and reduced a-motor neuron survival. Collectively, these results suggest that excessive axonal sprouting and motorunit (MU) expansion in female SOD1 G37R mice are maladaptive during ALS progression.Sex-specific differences in amyotrophic lateral sclerosis (ALS) progression have been identified in patients and in some animal models of the disease. However, the physio-pathologic changes underlying these disparities remain poorly defined. In this study, we identified that the pattern of motor axon retraction and regrowth in skeletal muscles is a novel factor to consider in our understanding of sex-linked differences in ALS. Analysis of single motor axons in a model of ALS identified that female motor axons were more likely to form compensatory branches, which was associated with a worse phenotype. These surprising findings highlight the necessity to more systematically evaluate the prevalence of sex-specific differences across animal models of ALS and in patients.

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Section: Discussionmentioning

confidence: 99%

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Martineau

Polo

Velde

et al. 2020

eNeuro

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“…Notably, we and others already evoked sex-mediated modifiers of C9ORF72 disease in FTD as well as in ALS. 11 , 20 , 21 Of interest, X-linked modifiers have also been recently suggested in other repeat expansion disorders such as spinocerebellar ataxia type 2 in which the residual heritability not explained by the expansion length seems to be partially driven by X-linked factors. 22 This may suggest common genetic mechanisms modulating AAO in repeat expansion diseases.…”

Section: Discussionmentioning

confidence: 99%

Factors influencing the age at onset in familial frontotemporal lobar dementia

et al. 2017

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Objective:To quantify the effect of genetic factors and generations influencing the age at onset (AAO) in families with frontotemporal lobar dementia (FTD) due to C9ORF72 hexanucleotide repeat expansions and GRN mutations.Methods:We studied 504 affected individuals from 133 families with C9ORF72 repeat expansions and 90 FTD families with mutations in GRN, 2 major genes responsible for FTD and/or amyotrophic lateral sclerosis. Intrafamilial correlations of AAO were analyzed, and variance component methods were used for heritability estimates. Generational effects on hazard rates for AAO were assessed using mixed-effects Cox proportional hazard models.Results:A generational effect influencing AAO was detected in both C9ORF72 and GRN families. Nevertheless, the estimated proportion of AAO variance explained by genetic factors was high in FTD caused by C9ORF72 repeat expansions (44%; p = 1.10e−4), 62% when the AAO of dementia was specifically taken into account (p = 8.10e−5), and to a lesser degree in GRN families (26%; p = 0.17). Intrafamilial correlation analyses revealed a significant level of correlations in C9ORF72 families according to the degree of kinship. A pattern of intrafamilial correlations also suggested potential X-linked modifiers acting on AAO. Nonsignificant correlation values were observed in GRN families.Conclusions:Our results provide original evidence that genetic modifiers strongly influence the AAO in C9ORF72 carriers, while their effects seem to be weaker in GRN families. This constitutes a rational to search for genetic biomarkers, which could help to improve genetic counseling, patient care, and monitoring of therapeutic trials.

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“…ALS shows sexual dimorphism in incidence, age of onset, and anatomical site of onset, with males usually having higher incidence, earlier age of onset, and presenting with spinal onset symptoms, as opposed to bulbar onset (McCombe & Henderson, ). While this evidence is largely based on cohorts of sporadic ALS patients, accounting for 90% of the disease, other evidence suggests a male predominance in familial ALS patients with SOD1 mutations (Kim et al, ) and C9orf72 repeat expansions (Rooney et al, ). Sex‐related effects are reproduced in the SOD1 G93A mouse model of ALS with males showing earlier disease onset with decreased survival, depending on the background strain (Pfohl, Halicek, & Mitchell, ).…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor antagonism accelerates disease onset in the SOD1^G93A mouse model of amyotrophic lateral sclerosis

McLeod

Lau

Chiam

et al. 2019

British J Pharmacology

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Background and Purpose Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease typically more common in males, implicating androgens in progression of both patients and mouse models. Androgen effects are mediated by androgen receptor which is highly expressed in spinal motor neurons and skeletal muscles. To clarify the role of androgen receptors in ALS, we therefore examined the effect of androgen receptor antagonism in the SOD1G93A mouse model. Experimental Approach The androgen receptor antagonist, flutamide, was administered to presymptomatic SOD1G93A mice as a slow‐release subcutaneous implant (5 mg·day−1). Testosterone, flutamide, and metabolite levels were measured in blood and spinal cord tissue by LC–MS–MS. Effects on disease onset and progression were assessed using motor function tests, survival, muscle, and neuropathological analyses. Key Results Flutamide was metabolised to 2‐hydroxyflutamide achieving steady‐state plasma levels across the study duration and reached the spinal cord at pharmacologically active concentrations. Flutamide treatment accelerated disease onset and locomotor dysfunction in male SOD1G93A mice, but not female mice, without affecting survival. Analysis of hindlimb muscles revealed exacerbation of myofibre atrophy in male SOD1G93A mice treated with flutamide, although motor neuron pathology was not affected. Conclusion and Implications The androgen receptor antagonist accelerated disease onset in male SOD1G93A mice, leading to exacerbated muscle pathology, consistent with a role of androgens in modulating disease severity, sexual dimorphism, and peripheral pathology in ALS. These results also demonstrate a key contribution of skeletal muscle pathology to disease onset, but not outcome, in this mouse model of ALS.

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C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis

Cited by 34 publications

References 31 publications

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Factors influencing the age at onset in familial frontotemporal lobar dementia

Androgen receptor antagonism accelerates disease onset in the SOD1^G93A mouse model of amyotrophic lateral sclerosis

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C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis

Cited by 34 publications

References 31 publications

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Factors influencing the age at onset in familial frontotemporal lobar dementia

Androgen receptor antagonism accelerates disease onset in the SOD1G93A mouse model of amyotrophic lateral sclerosis

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Androgen receptor antagonism accelerates disease onset in the SOD1^G93A mouse model of amyotrophic lateral sclerosis