Restricted loss of olivocochlear but not vestibular efferent neurons in the senescent gerbil (Meriones unguiculatus)

Degeneration of hearing and vertigo are symptoms of age related auditory and vestibular disorders reflecting multrfactorial changes in the peripheral and central nervous system whose interplay remains largely unknown. Originating bilaterally in the brain stem, vestibular and auditory efferent cholinergic projections exert feedback control on the peripheral sensory organs, and modulate sensory processing. We studied age-related changes in the auditory and vestibular efferent systems by evaluating number of cholinergic efferent neurons in young adult and aged gerbils, and in cholinergic trigeminal neurons serving as a control for efferents not related to the inner ear. We observed a significant loss of olivocochlear (OC) neurons in aged compared to young adult animals, whereas the overall number of lateral superior olive (LSO) cells was not reduced in aging. Although the loss of lateral and medial olivocochlear (MOC) neurons was uniform and equal on both sides of the brain, there were frequency-related differences within the lateral olivocochlear (LOC) neurons, where the decline was larger in the medial limb of the superior olivary nucleus (high frequency representation) than in the lateral limb (middle-to-low frequency representation). In contrast, neither the number of vestibular efferent neurons, nor the population of motor trigeminal neurons were significantly reduced in the aged animals. These observations suggest differential effects of aging on the respective cholinergic efferent brainstem systems

ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes

Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43Tg-ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy

ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes

Intermediate-length repeat expansions in ATXN-2 are the strongest genetic risk factor for ALS. Here, the authors combine patient-derived motor neurons and organoids with mouse models to dissect the pathogenic effects of ATXN2 intermediate expansions

Changes in miRNA expression profile in psoriatic skin during secukinumab treatment.

(A) Principal component analysis based on miRNA expression levels in individual patients from non-lesional and paired lesional psoriasis skin before (L D0) and after 4 (L D4), 14 (L D14), 42 (L D42), and 84 (L D84) days of treatment. (B) Heatmap with unsupervised hierarchical clustering of mean miRNA expression (as z-score of log-transformed values) between patients from non-lesional and paired lesional psoriasis skin dependent on the day of treatment. (C-E) MA plots depicting changes in miRNA levels between lesional and non-lesional skin (C), lesional skin before treatment (L D0), and lesional skin during secukinumab treatment on day 4 (D) or 14 (E). Depicted are the log2FC relative to mean expression. Multiple paired t-test with correction for multiple comparisons (FDR-Benjamini-Hochberg). (F) Volcano plots depicting changes in miRNA levels between lesional and non-lesional skin (left), lesional skin before treatment (L D0) and lesional skin during secukinumab treatment on day 4 (middle) or 14 (right). All colored dots depict miRNAs that were deregulated in lesional skin before treatment and were reversed in their expression pattern after 42 and/or 84 days of treatment (|log2FC|>0.5 and p-value1 and |log2FC|>0.5 (in both D0 and D84), respectively; n(NL, L D4, L D14, and L D43) = 14, n(L D0 and L D84) = 13. Depicted are only miRNAs with an average expression above 20 counts (n = 162).</p

Alterations in global circRNA expression in non-lesional (NL) and lesional (L) skin of psoriasis patients before and during secukinumab treatment.

(A-B) Principal component analysis based on circRNA expression levels in individual patients (A) and mean circRNA expression levels between patients (B) from non-lesional and paired lesional psoriasis skin before (L D0) and after 4 (L D4), 14 (L D14), 42 (L D42), and 84 (L D84) days of treatment. (C) Heatmap with unsupervised hierarchical clustering of mean circRNA expression (as z-score of log-transformed values) between patients from non-lesional and paired lesional psoriasis skin dependent on the day of treatment. (D-F) MA plots depicting changes in circRNA and mRNA levels between lesional D0 skin in contrast to non-lesional skin (D), as well as D4 (E) and D14 (F) in contrast to D0 lesional skin. Depicted are the normalized mean expression relative to the log2 fold change (log2FC); n(NL, L D4, L D14, and L D43) = 14, n(L D0) = 13, and n(L D84) = 12. All mRNAs are labelled (FUS, HNRNPL, DHX9, ADAR, and QKI).</p

Raw and normalized miRNA data for paired non-lesional and lesional skin of psoriasis patients before secukinumab treatment and healthy control skin.

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Changes in circRNA expression and ciRS-7 localization in non-lesional (NL) and lesional (L) skin of psoriasis patients before and during secukinumab treatment.

(A) Volcano plots show changes in specific circRNA and mRNA expression in lesional psoriasis skin before treatment (L D0; left) and during secukinumab treatment on day 42 (middle) and 84 (right). Plots depict adjusted (adj.) p-values relative to log2FC. Multiple paired t-test with correction for multiple comparisons (FDR-Benjamini-Hochberg); n(NL, L D4, L D14, and L D43) = 14, n(L D0) = 13, and n(L D84) = 12. Black points depict circRNAs with a |log2FC| > 1 and adj.-p-value FUS, HNRNPL, DHX9, ADAR, and QKI). (B) Hematoxylin staining combined with RNA CISH for ciRS-7 during treatment with secukinumab. Paired biopsies from non-lesional and lesional skin before (L D0), and 4, 14, 42, and 84 days after treatment initiation. Four micrometer sections of paraffin-embedded biopsies with one representative patient shown. Scale bar: 100 μm and 25 μm in zoom-in. (C) Boxplot showing the median log2FC of individual circRNAs in lesional D84 relative to D0 skin dependent on whether or not they characterize as Alu-mediated circRNA (presence of IAEs within 2300 nucleotide regions flanking the BSJs). Twenty circRNAs out of 48 circRNAs were considered Alu-mediated. Depicted are median values with whiskers extending to min. and max. values. Two-tailed Mann-Whitney test; n = 11. BSJ = backsplicing junction; CISH = chromogenic in situ hybridization; IAE = Inverted Alu elements.</p

Raw and normalized circRNA data for PBMCs isolated from psoriasis patients before and during secukinumab treatment.

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Raw and normalized circRNA data for paired non-lesional and lesional skin of psoriasis patients before secukinumab treatment and healthy control skin.

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Correlation between miR-203a-3p expression and cumulative miR-203a BSs on the circRNAs in individual patients during secukinumab treatment.

Correlation between miR-203a-3p expression and cumulative miR-203a BSs on the circRNAs in individual patients during secukinumab treatment.</p