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

Dols‐Icardo, Oriol; García‐Redondo, Alberto; Rojas‐García, Ricardo; Borrego-Hernández, Daniel; Illán-Gala, Ignacio; Muñoz-Blanco, José Luís; Rábano, Alberto; Cervera-Carles, Laura; Juárez-Rufián, Alexandra; Spataro, Nino; Luna, Noemí de; Galán, Lucía; Cortés-Vicente, Elena; Fortea, Juan; Blesa, Rafael; Grau‐Rivera, Oriol; Lleó, Alberto; Esteban-Pérez, Jesús; Gelpí, Ellen; Clarimón, Jordi

doi:10.1136/jnnp-2017-316820

Cited by 55 publications

(40 citation statements)

References 41 publications

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“…Thus, their change of expression in ALS could be related with the pathology [190]. Moreover, mutations in ErbB4 have been described in autosomal dominant familial and sporadic forms of ALS [191] with concomitant frontotemporal dementia [192]. This supports a possible pathogenic role of ErbB4 in ALS [193].…”

Section: Erbbmentioning

confidence: 77%

The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling

Lanuza

Just-Borràs

Hurtado

et al. 2019

Cells

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Brain-derived neurotrophic factor (BDNF) promotes neuron survival in adulthood in the central nervous system. In the peripheral nervous system, BDNF is a contraction-inducible protein that, through its binding to tropomyosin-related kinase B receptor (TrkB), contributes to the retrograde neuroprotective control done by muscles, which is necessary for motor neuron function. BDNF/TrkB triggers downstream presynaptic pathways, involving protein kinase C, essential for synaptic function and maintenance. Undeniably, this reciprocally regulated system exemplifies the tight communication between nerve terminals and myocytes to promote synaptic function and reveals a new view about the complementary and essential role of pre and postsynaptic interplay in keeping the synapse healthy and strong. This signaling at the neuromuscular junction (NMJ) could establish new intervention targets across neuromuscular diseases characterized by deficits in presynaptic activity and muscle contractility and by the interruption of the connection between nervous and muscular tissues, such as amyotrophic lateral sclerosis (ALS). Indeed, exercise and other therapies that modulate kinases are effective at delaying ALS progression, preserving NMJs and maintaining motor function to increase the life quality of patients. Altogether, we review synaptic activity modulation of the BDNF/TrkB/PKC signaling to sustain NMJ function, its and other kinases’ disturbances in ALS and physical and molecular mechanisms to delay disease progression.

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Section: Erbbmentioning

confidence: 77%

The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling

Lanuza

Just-Borràs

Hurtado

et al. 2019

Cells

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“…The other (patient 14) had a prominent amygdalar gliosis. A detailed description of the neuropathological examination of this patient was previously reported [17]. Concomitant pathologies were observed in 2 patients (patients 3 and 19) in the form of argyrophilic grain pathology or as primary age-related tauopathy with mild or without β-amyloid deposits.…”

Section: Resultsmentioning

confidence: 99%

“…A family history of ALS or FTD was not always seen in those with a causative mutation. A recent exome-wide sequencing study on patients with MND-FTD reported similar rates of mutation and revealed a highly heterogeneous mutation landscape in MND-FTD patients [17]. Cumulative evidence indicates a high genetic background underlying the co-occurrence of MND and FTD, and suggests that testing ALS- and FTD-associated genetic loci should be considered with those patients, regardless of any family history of the disease [23].…”

Section: Discussionmentioning

confidence: 99%

Distinct Clinical Features and Outcomes in Motor Neuron Disease Associated with Behavioural Variant Frontotemporal Dementia

Cortés-Vicente

Turón-Sans

Gelpí

et al. 2018

Dement Geriatr Cogn Disord

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Aim: To determine the motor phenotype and outcome in a clinically ascertained group of patients with motor neuron disease (MND) and frontotemporal dementia (FTD). Methods: This is an observational retrospective clinical study of patients fulfilling the clinical criteria for MND-FTD. A contemporary series of patients with amyotrophic lateral sclerosis (ALS) without dementia were included for comparison. Demographic, clinical, genetic, and neuropathological data were collected. A descriptive and comparative data analysis was performed. Results: We identified 22 patients with MND-FTD. Selective distal upper limb muscle weakness and atrophy with non-significant lower limb weakness during follow-up was the most frequent motor pattern, present in 18 patients – in 15 of them associated with severe dysphagia. Aspiration pneumonia was the most common cause of death (12/19; 63%) despite gastrostomy. One-third of the patients did not develop upper motor neuron dysfunction. When compared to classic ALS without dementia (n = 162), these features were significantly different. A neuropathological examination was performed on 7 patients, and it confirmed the presence of MND with TDP43 protein aggregates in all patients. Conclusions: The MND-FTD patients frequently displayed a distinctive motor pattern characterized by weakness and atrophy in distal upper limb muscles and dysphagia, with no or little spreading to other regions. These features may help to define specific subgroups of patients, which is important with regard to clinical management, outcome, and research.

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“…ALS is a complex multisystem neurodegenerative disease seen in comorbidity with a wide range of cognitive and behavioral abnormalities, ranging 15 to 50% of cases (Montuschi et al, 2015;Cui et al, 2015), and particularly overlapping with frontotemporal dementia (FTD) (Lillo and Hodges, 2010). Possible pathogenic mutations in ERBB4 gene has been also recently described in concomitant ALS and FTD (Dols-Icardo et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Decreased circulating ErbB4 ectodomain fragments as a read-out of impaired signaling function in amyotrophic lateral sclerosis

López-Font

Sogorb‐Esteve

Javier-Torrent

et al. 2019

Neurobiology of Disease

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ErbB4 is a transmembrane receptor tyrosine kinase that binds to neuregulins to activate signaling. Proteolytic cleavage of ErbB4 results in release of soluble fragments of ErbB4 into the interstitial fluid. Disruption of the neuregulin-ErbB4 pathway has been suggested to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). This study assesses whether soluble proteolytic fragments of the ErbB4 ectodomain (ecto-ErbB4) can be detected in cerebrospinal fluid (CSF) and plasma, and if the levels are altered in ALS. Immunoprecipitation combined with mass spectrometry or western blotting analyses confirmed the presence of ecto-ErbB4 in human CSF. Several anti-ErbB4-reactive bands, including a 55 kDa fragment, were detected in CSF. The bands were generated in the presence of neuregulin-1 (Nrg1) and were absent in plasma from ErbB4 knockout mice. Ecto-ErbB4 levels were decreased in CSF from ALS patients (n = 20) and ALS with concomitant frontotemporal dementia patients (n = 10), compared to age-matched controls (n = 13). A similar decrease was found for the short ecto-ErbB4 fragments in plasma of the same subjects. Likewise, the 55-kDa ecto-ErbB4 fragments were decreased in the plasma of the two transgenic mouse models of ALS (SOD1G93A and TDP-43A315T). Intracellular ErbB4 fragments were decreased in the frontal cortex from SOD1G93A mice, indicating a reduction in Nrg-dependent induction of ErbB4 proteolytic processing, and suggesting impaired signaling. Accordingly, overexpression of Nrg1 induced by an adeno-associated viral vector increased the levels of the ecto-ErbB4 fragment in the SOD1G93A mice. We conclude that the determination of circulating ecto-ErbB4 fragments could be a tool to evaluate the impairment of the ErbB4 pathway and may be a useful biomarker in ALS.

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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

Cited by 55 publications

References 41 publications

The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling

The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling

Distinct Clinical Features and Outcomes in Motor Neuron Disease Associated with Behavioural Variant Frontotemporal Dementia

Decreased circulating ErbB4 ectodomain fragments as a read-out of impaired signaling function in amyotrophic lateral sclerosis

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