Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS

Takahashi, Yūji; Uchino, Akira; Shioya, Ayako; Sano, Tadahiro; Matsumoto, Chihiro; Numata‐Uematsu, Yurika; Nagano, Seiichi; Araki, Toshiyuki; Murayama, Shigeo; Saito, Yuko

doi:10.1111/neup.12558

Cited by 19 publications

(16 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This pathway regulates cell proliferation, migration, differentiation, and apoptosis via MAPK, Akt, and related pathways. ErbB4 is also implicated in familial and sporadic ALS and altered in sporadic ALS spinal cord tissue (Takahashi et al, 2013(Takahashi et al, , 2019Dols-Icardo et al, 2018;Narain et al, 2019). ErbB tyrosine kinase receptors bind neuregulins, neurotrophic factors highly expressed in the CNS, which play a critical role in motor neuron function and survival (Mautino et al, 2004;Schram et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Figueroa‐Romero

Hur

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a terminalneurodegenerative disease. Clinical and molecular observations suggest that ALS pathology originates at a single site and spreads in an organized and prion-like manner, possibly driven by extracellular vesicles. Extracellular vesicles (EVs) transfer cargo molecules associated with ALS pathogenesis, such as misfolded and aggregated proteins and dysregulated microRNAs (miRNAs). However, it is poorly understood whether altered levels of circulating extracellular vesicles or their cargo components reflect pathological signatures of the disease. In this study, we used immuno-affinity-based microfluidic technology, electron microscopy, and NanoString miRNA profiling to isolate and characterize extracellular vesicles and their miRNA cargo from frontal cortex, spinal cord, and serum of sporadic ALS (n = 15) and healthy control (n = 16) participants. We found larger extracellular vesicles in ALS spinal cord versus controls and smaller sized vesicles in ALS serum. However, there were no changes in the number of extracellular vesicles between cases and controls across any tissues. Characterization of extracellular vesicle-derived miRNA cargo in ALS compared to controls identified significantly altered miRNA levels in all tissues; miRNAs were reduced in ALS frontal cortex and spinal cord and increased in serum. Two miRNAs were dysregulated in all three tissues: miR-342-3p was increased in ALS, and miR-1254 was reduced in ALS. Additional miRNAs overlapping across two tissues included miR-587, miR-298, miR-4443, and miR-450a-2-3p. Predicted targets and pathways associated with the dysregulated miRNAs across the ALS tissues were associated with common biological pathways altered in neurodegeneration, including axon guidance and long-term potentiation. A predicted target of one identified miRNA (N-deacetylase and N-sulfotransferase 4; NDST4) was likewise dysregulated in an in vitro model of ALS, verifying potential biological relevance. Together, these findings demonstrate that circulating extracellular vesicle miRNA cargo mirror those of the central nervous system disease state in ALS, and thereby offer insight into possible pathogenic factors and diagnostic opportunities.

show abstract

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Figueroa‐Romero

Hur

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…A heterozygous mutation in ERBB4 (c.2136T>G, p.Ile712Met) was also reported in late-onset alS/FTD ( 18 ). Moreover, in the pathophysiology of ALS, immunofluorescence staining showed that ERBB4 immunoreactivity was decreased in the spinal cord of sALS patients, which further indicates that ERBB4 is involved in the pathophysiological process of sALS ( 19 ). In this study, we screened ERBB4 variants in a large cohort of ALS patients from mainland China to determine their pathogenicity and frequency.…”

Section: Introductionmentioning

confidence: 92%

Analysis of ERBB4 Variants in Amyotrophic Lateral Sclerosis Within a Chinese Cohort

Wang

Liu

et al. 2022

Front. Neurol.

View full text Add to dashboard Cite

ERBB4 is related to amyotrophic lateral sclerosis (ALS) in patients with a family history and is thought to cause ALS-19. We screened 448 ALS patients, including 364 sporadic ALS (sALS) and 84 familial ALS (fALS) patients with ERBB4 variants, in a Chinese cohort. In total, 12 missense variants were identified in this study. Of these, 3 (p.Arg106His, p.Gln164Pro, and p.Val212Leu) were absent from the in-house healthy control cohort and population databases and predicted to be likely pathogenic. Genetic burden analysis did not reveal an increase in damaging variants of the ERBB4 gene. We considered that most of the missense variants in ERBB4 were not pathogenic, but certain variants, such as p.Arg106His, p.Gln164Pro, and p.Val212Leu, were likely pathogenic. The phenotype of these three patients carrying ERBB4 variants revealed the typical clinical manifestations of ALS without cognitive dysfunction. We concluded that ERBB4 likely pathogenic variants account for ~0.67% of ALS patients in China. It is necessary to interpret the relationship between the disease and variants carefully for ALS patients with ERBB4 gene variants.

show abstract

“…An ectopic oligodendroglial ErBB4 immunoreactivity could also be detected. Interestingly, the expression of ErBB4 and TDP-43 appeared to be mutually exclusive in oligodendrocytes [ 106 ].…”

Section: Pathological Inclusions In Oligodendrocytes From Als Patimentioning

confidence: 99%

Defective Oligodendroglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis

Traiffort

Morisset-Lopez

Moussaed

et al. 2021

IJMS

View full text Add to dashboard Cite

Motor neurons and their axons reaching the skeletal muscle have long been considered as the best characterized targets of the degenerative process observed in amyotrophic lateral sclerosis (ALS). However, the involvement of glial cells was also more recently reported. Although oligodendrocytes have been underestimated for a longer time than other cells, they are presently considered as critically involved in axonal injury and also conversely constitute a target for the toxic effects of the degenerative neurons. In the present review, we highlight the recent advances regarding oligodendroglial cell involvement in the pathogenesis of ALS. First, we present the oligodendroglial cells, the process of myelination, and the tight relationship between axons and myelin. The histological abnormalities observed in ALS and animal models of the disease are described, including myelin defects and oligodendroglial accumulation of pathological protein aggregates. Then, we present data that establish the existence of dysfunctional and degenerating oligodendroglial cells, the chain of events resulting in oligodendrocyte degeneration, and the most recent molecular mechanisms supporting oligodendrocyte death and dysfunction. Finally, we review the arguments in support of the primary versus secondary involvement of oligodendrocytes in the disease and discuss the therapeutic perspectives related to oligodendrocyte implication in ALS pathogenesis.

show abstract

Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS

Cited by 19 publications

References 46 publications

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Analysis of ERBB4 Variants in Amyotrophic Lateral Sclerosis Within a Chinese Cohort

Defective Oligodendroglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About