Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

Abstract Microglia are the resident mononuclear phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in mononuclear phagocytes are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT2B), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphi...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

Related Links:

Conclusions This study demonstrates that cerebral degeneration in ALS is more pronounced in the motor than prefrontal cortex, that multicenter MRS studies are feasible, and that motor tNAA/Ino shows promise as a potential biomarker.
Source: Neurology Clinical Practice - Category: Neurology Authors: Tags: MRI, MRS, Amyotrophic lateral sclerosis Research Source Type: research
.
Source: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration - Category: Neurology Authors: Source Type: research
Objective To test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) inheriting the common interleukin 6 receptor (IL6R) coding variant (Asp358Ala, rs2228145, C allele) have associated increases in interleukin 6 (IL6) and IL6R levels in serum and CSF and faster disease progression than noncarriers. Methods An observational, case-control study of paired serum and CSF of 47 patients with ALS, 46 healthy, and 23 neurologic disease controls from the Northeastern ALS Consortium Biofluid Repository (cohort 1) was performed to determine serum levels of IL6, sIL6R, and soluble glycoprotein 130 and compared acro...
Source: Neurology Neuroimmunology and Neuroinflammation - Category: Neurology Authors: Tags: All Immunology, All Clinical Neurology, Amyotrophic lateral sclerosis, All Genetics Article Source Type: research
Publication date: Available online 11 October 2019Source: Neurophysiologie CliniqueAuthor(s): Chaojun Zheng, Yu Zhu, Minghao Shao, Dongqing Zhu, Hong Hu, Kai Qiao, Jianyuan JiangSummaryObjectivesTo investigate and compare split-hand phenomenon quantified by motor unit number index (MUNIX) between patients with cervical spondylotic amyotrophy (CSA) and those with amyotrophic lateral sclerosis (ALS).MethodsMUNIX was performed on abductor pollicis brevis (APB), abductor digiti minimi (ADM) and first dorsal interosseous (FDI) in 46 CSA patients, 39 ALS patients and 41 healthy subjects. Split-hand measurements including split-h...
Source: Neurophysiologie Clinique - Category: Neuroscience Source Type: research
This study presents a novel method of targeted DNA methylation that utilizes endogenous DNA double strand break repair pathways and applies it to the neurodegenerative disease gene C9orf72. A double strand break induced by CRISPR/cas9 in the promoter of C9orf72 is sufficient to induce DNA methylation, and methylation can be precisely targeted through the process of homology directed repair (HDR) via delivery of an in vitro methylated exogenous repair template. Long methylated double stranded DNA templates induce more methylation than shorter templates and with higher efficiency than a dCas9-DNMT3a fusion protein construct....
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Methylation profiling by genome tiling array Homo sapiens Source Type: research
This study presents a novel method of targeted DNA methylation that utilizes endogenous DNA double strand break repair pathways and applies it to the neurodegenerative disease gene C9orf72. A double strand break induced by CRISPR/cas9 in the promoter of C9orf72 is sufficient to induce DNA methylation, and methylation can be precisely targeted through the process of homology directed repair (HDR) via delivery of an in vitro methylated exogenous repair template. Long methylated double stranded DNA templates induce more methylation than shorter templates and with higher efficiency than a dCas9-DNMT3a fusion protein construct....
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Methylation profiling by genome tiling array Homo sapiens Source Type: research
The angiogenin (ANG) gene is mutated frequently in individuals with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Delivering human ANG to mice that display ALS-like symptoms extends their lifespan and improves motor function. ANG is a secretory vertebrate RNase that enters neuronal cells and cleaves a subset of tRNAs, leading to the inhibition of translation initiation and the assembly of stress granules. Here, using murine neuronal and astrocytic cell lines, we find that ANG triggers the activation of the Nrf2 (nuclear factor erythroid 2-rela...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Neurobiology Source Type: research
Nature Reviews Neurology, Published online: 11 October 2019; doi:10.1038/s41582-019-0276-zUltrasound success removes barriers to targeted drug delivery in amyotrophic lateral sclerosis
Source: Nature Reviews Neurology - Category: Neurology Authors: Source Type: research
ConclusionsIn this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD.
Source: PLoS Medicine - Category: Internal Medicine Authors: Source Type: research
.
Source: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration - Category: Neurology Authors: Source Type: research
More News: ALS | Genetics | Neurology