Reduced expression of mitochondrial fumarate hydratase in progressive multiple sclerosis contributes to impaired in vitro mesenchymal stromal cell-mediated neuroprotection

BACKGROUND: Cell-based therapies for multiple sclerosis (MS), including those employing autologous bone marrow-derived mesenchymal stromal cells (MSC) are being examined in clinical trials. However, recent studies have identified abnormalities in the MS bone marrow microenvironment. OBJECTIVE: We aimed to compare the secretome of MSC isolated from control subjects (C-MSC) and people with MS (MS-MSC) and explore the functional relevance of findings. METHODS: We employed high throughput proteomic analysis, enzyme-linked immunosorbent assays and immunoblotting, as well as in vitro assays of enzyme activity and neuroprotection. RESULTS: We demonstrated that, in progressive MS, the MSC secretome has lower levels of mitochondrial fumarate hydratase (mFH). Exogenous mFH restores the in vitro neuroprotective potential of MS-MSC. Furthermore, MS-MSC expresses reduced levels of fumarate hydratase (FH) with downstream reduction in expression of master regulators of oxidative stress. CONCLUSIONS: Our findings are further evidence of dysregulation of the bone marrow microenvironment in progressive MS with respect to anti-oxidative capacity and immunoregulatory potential. Given the clinical utility of the fumaric acid ester dimethyl fumarate in relapsing–remitting MS, our findings have potential implication for understanding MS pathophysiology and personalised therapeutic intervention

Discovery of s-process enhanced stars in the LAMOST survey

Here we present the discovery of 895 s-process-rich candidates from 454 180 giant stars observed by the Large Sky Area Multi-Object Fibre Spectroscopic Telescope (LAMOST) using a data-driven approach. This sample constitutes the largest number of s-process enhanced stars ever discovered. Our sample includes 187 s-process-rich candidates that are enhanced in both barium and strontium, 49 stars with significant barium enhancement only and 659 stars that show only a strontium enhancement. Most of the stars in our sample are in the range of effective temperature and log g typical of red giant branch (RGB) populations, which is consistent with our observational selection bias towards finding RGB stars. We estimate that only a small fraction (∼0.5 per cent) of binary configurations are favourable for s-process enriched stars. The majority of our s-process-rich candidates (95 per cent) show strong carbon enhancements, whereas only five candidates (<3  per cent) show evidence of sodium enhancement. Our kinematic analysis reveals that 97 per cent of our sample are disc stars, with the other 3 per cent showing velocities consistent with the Galactic halo. The scaleheight of the disc is estimated to be z_h = 0.634±0.063kpc⁠, comparable with values in the literature. A comparison with yields from asymptotic giant branch (AGB) models suggests that the main neutron source responsible for the Ba and Sr enhancements is the ¹³C(α,n)¹⁶O reaction. We conclude that s-process-rich candidates may have received their overabundances via mass transfer from a previous AGB companion with an initial mass in the range 1−3M_⊙

On the discovery of K-enhanced and possibly Mg-depleted stars throughout the Milky Way

Stars with unusual elemental abundances offer clues about rare astrophysical events or nucleosynthetic pathways. Stars with significantly depleted magnesium and enhanced potassium ([Mg/Fe] 1) have to date only been found in the massive globular cluster NGC 2419 and, to a lesser extent, NGC 2808. The origin of this abundance signature remains unknown, as does the reason for its apparent exclusivity to these two globular clusters. Here we present 112 field stars, identified from 454 180 LAMOST giants, that show significantly enhanced [K/Fe] and possibly depleted [Mg/Fe] abundance ratios. Our sample spans a wide range of metallicities (−1.5 < [Fe/H] < 0.3), yet none show abundance ratios of [K/Fe] or [Mg/Fe] that are as extreme as those observed in NGC 2419. If confirmed, the identified sample of stars represents evidence that the nucleosynthetic process producing the anomalous abundances ratios of [K/Fe] and [Mg/Fe] probably occurs at a wide range of metallicities. This would suggest that pollution scenarios that are limited to early epochs (such as Population III supernovae) are an unlikely explanation, although they cannot be ruled out entirely. This sample is expected to help guide modelling attempts to explain the origin of the Mg–K abundance signature

Abnormal scaffold attachment factor 1 expression and localisation in spinocerebellar ataxias and huntington’s chorea

SAFB1 is a DNA and RNA binding protein that is highly expressed in the cerebellum and hippocampus and is involved in the processing of coding and non‐coding RNAs, splicing and dendritic function. We analyzed SAFB1 expression in the post‐mortem brain tissue of spinocerebellar ataxia (SCA), Huntington’s disease (HD), Multiple sclerosis (MS), Parkinson’s disease patients and controls. In SCA cases, the expression of SAFB1 in the nucleus was increased and there was abnormal and extensive expression in the cytoplasm where it co‐localized with the markers of Purkinje cell injury. Significantly, no SAFB1 expression was found in the cerebellar neurons of the dentate nucleus in control or MS patients; however, in SCA patients, SAFB1 expression was increased significantly in both the nucleus and cytoplasm of dentate neurons. In HD, we found that SAFB1 expression was increased in the nucleus and cytoplasm of striatal neurons; however, there was no SAFB1 staining in the striatal neurons of controls. In PD substantia nigra, we did not see any changes in neuronal SAFB1 expression. iCLIP analysis found that SAFB1 crosslink sites within ATXN1 RNA were adjacent to the start and within the glutamine repeat sequence. Further investigation found increased binding of SAFB1 to pathogenic ATXN1‐85Q mRNA. These novel data strongly suggest SAFB1 contributes to the etiology of SCA and Huntington’s chorea and that it may be a pathological marker of polyglutamine repeat expansion diseases

Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro

Background: Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised. Objectives: To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS. Methods: Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken. Results: In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of β-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro. Conclusion: Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS. </jats:sec