Biology subjects

Almaguer-Mederos, L. E.

Publications and source records attributed to Almaguer-Mederos, L. E..

6 recordsLinked to original sources

bioRxiv2026

Blood glucose homeostasis in patients with mild to moderate Spinocerebellar Ataxia type 2

BackgroundSpinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder that shows cerebellar glucose hypometabolism, systemic hypermetabolism and weight loss. This study aimed to explore novel molecular biomarker candidates for SCA2, based on the assessment of blood glucose homeostasis. MethodsA case-control and correlational study was conducted in 79 Cuban patients with SCA2 and 83 sex- and age-matched control subjects during a fasting state. A subset of 20 SCA2 patients and 19 control individuals underwent an oral glucose tolerance test (OGTT). Several indices for assessing blood glucose homeostasis, derived from the fasting state or the OGTT, were included in the study. ResultsFasting glucose levels showed a small increase, whereas the QUICKI index for insulin sensitivity was slightly decreased among patients. Markers of glucose homeostasis derived from the OGTT were no different between patients and controls. Fasting insulin levels, QUICKI, McAuleys, HOMA2-%S, HOMA2-IR, and HOMA2-%{beta} indices showed weak to moderate correlations with markers of body composition. McAuleys, TyG, HOMA2-IR, and HOMA2-%{beta} indices correlated with the age at onset, progression rate, or INAS count. ConclusionsSCA2 patients with mild to moderate ataxia do not have any major alteration in blood glucose homeostasis. Markers of glucose homeostasis associate with body composition and has modifying effects on disease severity and progression rate in patients with SCA2, with McAuleys index showing effects more consistently. Further studies are needed to describe the changes in blood glucose homeostasis in the different stages of disease, and to confirm the validity of McAuleys index as a candidate biomarker for SCA2 clinical severity and progression.

physiology↗

bioRxiv2025

ATXN2 polyglutamine expansion impairs QKI-dependent alternative splicing and oligodendrocyte maintenance

BackgroundPolyglutamine (polyQ) tract expansion mutations in Ataxin-2 gene (ATXN2) are associated with neurodegenerative diseases spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS), while the therapeutic reduction of ATXN2 confers strong health-/lifespan extension in models of both disorders. Although the involvement of ATXN2 in peripheral lipid metabolism has been elaborated in Atxn2 knock-out mice, its impact on nervous system lipid maintenance and a potential influence on oligodendrocytes remains unexplored. MethodsWe examine the nervous tissue of an authentic ATXN2 polyQ expansion mouse model in terms of (i) gross morphology of the brain and differential glial affection via immunohistochemical analyses, (ii) spinocerebellar proteome profile via label-free mass spectroscopy and (iii) alternative splicing patterns of oligodendroglial transcripts via quantitative RT-PCR. Finally, electrophysiological recording of sensory response in cerebellar Purkinje cells was performed as a phenotypic measure of demyelination. ResultsWe demonstrate a massive impairment in myelin maintenance due to ATXN2 polyQ expansion, affecting key oligodendroglial proteins accompanied by their splicing anomalies much earlier than disease manifestation. Oligodendroglial ATXN2 aggregates were documented for the first time in cerebellum, which sequestrated the RNA splicing factor Quaking (QKI). As an outcome of demyelination, our SCA2 model showed a significant delay in response to sensory stimuli. ConclusionsOverall, we provide pioneer evidence of oligodendroglial proteotoxicity leading to myelin maintenance defects in an authentic mouse model of SCA2. Our findings suggest that not only neuronal metabolism, but also that of oligodendroglia depends on ATXN2 and is affected during the disease course. This novel aspect of ATXN2 pathomechanism sheds light on potential outcomes of its therapeutic manipulation, and makes it relevant also for demyelination syndromes next to SCA2 and other polyQ disorders.

neuroscience↗

bioRxiv2025

Multiomics approach identifies SERPINB1 as candidate progression biomarker for Spinocerebellar Ataxia type 2

BackgroundSpinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder, and variants in its disease protein Ataxin-2 act as modifiers in the progression of Amyotrophic Lateral Sclerosis. There are no reliable molecular progression biomarkers for SCA2. ObjectivesThe aim of this study was to define novel molecular progression biomarker candidates for SCA2. MethodsUsing cerebellar and cervicothoracic spinal cord RNA from Atxn2-CAG100-KnockIn and wildtype mice, a multi-omics study was conducted, followed by validation in mice and humans. Global transcriptome studies were conducted using the Clariom D microarray. Extracted proteins were analyzed by LC-MS/MS for global proteomics, and Immobilized Metal Affinity Chromatography for phosphoproteomics. Validation assessed expression by RT-qPCR, and protein abundance by quantitative immunoblots and ELISA. Patients with SCA2 were diagnosed following standard procedures, and the age at onset, SARA score, INAS count, and disease duration were used as clinical severity markers. ResultsVenn diagram comparisons across all OMICS datasets indicated that only Serpinb1a-transcript, SERPINB1A-protein and -phosphopeptides were consistently downregulated at terminal stage in 14-month-old KnockIn mice. Expression studies in cerebellum and spinal cord from 10 weeks (pre-manifest), 6-month-old (early ataxic), and 14-month-old (late ataxic stage) mice confirmed this progressive decrease at mRNA and protein level. SERPINB1 plasma levels were significantly lower in SCA2 patients, and displayed a significant association with the CAG repeat length at expanded ATXN2 alleles and the age at onset, also showing a trend towards significance with the SARA score. ConclusionsSERPINB1 was identified as novel promising biomarker with specificity for SCA2 pathomechanisms.

molecular biology↗

bioRxiv2025

ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation

The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly nuclear, more abundant, and essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. In this study, we utilized two approaches to clarify the roles of ATXN2L. First, we identified interactors through co-immunoprecipitation in both wild-type and ATXN2L-null murine embryonic fibroblasts. Second, we assessed the proteome profile effects using mass spectrometry in these cells. Additionally, we examined the accumulation of ATXN2L interactors in the SCA2 mouse model, Atxn2-CAG100-KnockIn (KIN). We observed that RNA-binding proteins, including PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL, exhibit a stronger association with ATXN2L compared to established interactors like ATXN2, PABPC1, LSM12, and G3BP2. Additionally, ATXN2L interacted with components of the actin complex, such as SYNE2, LMOD1, ACTA2, FYB, and GOLGA3. We noted that oxidative stress increased HNRNPK but decreased SYNE2 association, which likely reflects the relocalization of SG. Proteome profiling revealed that NUFIP2 and SYNE2 are depleted in ATXN2L-null fibroblasts. Furthermore, NUFIP2 homodimers and SYNE1 accumulate during the ATXN2 aggregation process in KIN 14-month-old spinal cord tissues. The functions of ATXN2L and its interactors are therefore critical in RNA granule trafficking and surveillance, particularly for the maintenance of differentiated neurons.

molecular biology↗

bioRxiv2024

Spinal cord phosphoproteome of a SCA2/ALS13 mouse model reveals alteration of ATXN2-N-term SH3-actin interactome and of autophagy via WNK1-MYO6-OPTN-SQSTM1

Toxic polyglutamine (polyQ) expansions in ATXN2 trigger neurodegenerative processes, causing Spinocerebellar Ataxia type 2 (SCA2), and enhancing TDP-43-dependent pathology in Amyotrophic Lateral Sclerosis (ALS) / Fronto-Temporal Dementia (FTD). Primary disease events can be compensated transiently, delaying disease manifestation. To define potential therapy targets, we documented how cells modify their phospho-signals and how the ATXN2 interactome changes, using preferentially affected nervous tissues from end-stage Atxn2-CAG100-KnockIn mice. The spinal cord phosphorylome revealed massive hyperphosphorylations flanking the polyQ expansion in ATXN2 and for SQSTM1, and moderate hyperphosphorylations also for ALS proteins OPTN, UBQLN2, TNIP1 and TBK1-targeted TAX1BP1, versus strong hypophosphorylations of WNK1, SPARCL1 and PSMD9. Significant enrichments of SH3-containing proteins, autophagy / endocytosis factors, and actin modulators could be explained by N-terminal, polyQ-adjacent, proline-rich motifs in ATXN2. Coimmunoprecipitation profiling in cerebellum documented known associations with RNA-binding proteins like PABPC1 and TDP-43 with its modifier PPIA to decrease upon expansion, contrasting with increased binding of SH3-proteins, like MYO6, RPL21 and DLG4. Validation of protein and mRNA levels in mouse spinal cord, and embryonic fibroblasts or patient fibroblasts after bafilomycin or arsenite treatment, observed polyQ-dependent OPTN deficiency and SQSTM1 induction impairment. Overall, this combined phosphoproteome / interactome study efficiently revealed key pathways and molecular events.

molecular biology↗

bioRxiv2018

Atxn2-CAG100-knock-in affects mouse lifespan and vestibulo-cerebellar function via neural disconnection

Unstable expansions in the Q22-polyglutamine domain of human ATXN2 mediate risks for motor neuron diseases such as ALS/FTLD or cause the autosomal dominant Spinocerebellar Ataxia type 2 (SCA2), but the pathogenesis is not understood and models are unavailable.\n\nWe generated a novel knock-in mouse line with CAG100 expansion in Atxn2, transmitted unstably. The mutant protein accumulated in neuronal cytosolic aggregates, with a characteristic pattern of multi-system-atrophy. Loss-of-function phenotypes included less mutant offspring, initial weight gain and motor hyperactivity. Progressive toxic aggregation effects started around 20 weeks in homozygous animals showing weight loss, reduced muscle strength and gait ataxia. Lifespan was decreased. In the cerebellum, neuronal soma and dendrites were remarkably spared. However, myelin proteins MBP, CNP, PLP1 and transcripts Mal, Mobp, Rtn4 decreased markedly, especially adhesion factors MAG and MOG. In neurons, strong reductions were found for mRNAs of perineuronal elements Haplnl, Hapln2, Hapln4, of axonal myelin interactors Prnp and Klk6. At protein level, the adhesion factor neuroplastin and neurofilaments were strongly reduced, while presynaptic alpha-synuclein increased two-fold.\n\nOverall, this authentic SCA2 mouse model elucidates how altered function and aggregation toxicity of ATXN2 conspire to trigger axon-myelin disconnection. This model will promote the development of neuroprotective therapies and disease biomarkers.

neuroscience↗