Biology subjects

Guerreiro, S.

Publications and source records attributed to Guerreiro, S..

4 recordsLinked to original sources

bioRxiv2026

Understanding corticosterone fluctuations and HPA-axis regulation in a mouse model of Spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph Disease (MJD) is a neurodegenerative disease caused by a CAG triplet expansion in the ATXN3 gene, primarily characterized by motor impairments. However, SCA3/MJD also includes mood-related comorbidities that affect both patients and their caregivers. Current treatments focus on symptom management and supportive care, as no disease-modifying therapies are available. Previously, we have demonstrated decreased glucocorticoid receptor (GR) expression in post-mortem SCA3 human and mouse brains and elevated peripheral corticosterone (CORT) levels in SCA3 mice at late disease stages. Impaired GR signaling is typically associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, common in stress-related psychiatric diseases. Our study aimed to dissect the HPA-axis (dys)function and the effect of stress exposure on SCA3/MJD progression. Using the CMVMJD135 mouse model, we evaluated HPA-axis regulation in SCA3/MJD by measuring CORT levels throughout disease progression (6 to 34 weeks of age) under basal conditions and after acute stress. At week 35, these mice underwent a dexamethasone injection to challenge the HPA-axis, and the CORT levels were measured at different timepoints to evaluate the axis response. Additionally, we applied a 6-week chronic unpredictable stress (CUS) protocol in another cohort of mice starting at an early symptomatic stage to assess stress effects on the progression of motor impairments. Our findings indicate that serum CORT levels in SCA3 mice begin to rise between 26 to 30 weeks of age, with no impairment in the physiological response to acute stress. SCA3 mice were also able to normalize CORT levels after dexamethasone challenge, suggesting normal HPA-axis function. While CUS exposure had a transient negative impact on the motor phenotype, this effect did not persist throughout disease progression. In conclusion, stressful events, either acute or chronic, do not seem to be major determinants of disease severity in SCA3 mice.

neuroscience↗

bioRxiv2025

The 5-HT1A receptor agonist NLX-112 rescues motor swimming deficits in Spinocerebellar Ataxia type 3 mice

IntroductionSpinocerebellar ataxia 3 (SCA3) is a rare neurodegenerative disorder which causes progressive motor disturbances. There is no approved drug treatment but selective activation of serotonin 5-HT1A receptors may be a promising therapeutic strategy to attenuate ataxia symptoms. MethodsNLX-112, a highly selective 5-HT1A full agonist, was tested in the CMVMJD135 transgenic mouse model of SCA3. NLX-112 (1.25 and 5 mg/kg/day) was administered BID intraperitoneally for 14 weeks starting when the mice were 12 weeks of age, i.e., after ataxia signs had become established. The motor swimming test (MST), where mice are required to swim to a raised platform, was used to evaluate the motor behavior of SCA3 mice and their performance was compared with that of wild-type (WT) mice. ResultsBoth doses of NLX-112 were well tolerated by the SCA3 mice, as assessed by welfare parameters. In the MST, the latency of SCA3 mice to reach the platform was significantly longer than that of WT mice. However, when SCA3 mice were treated with either 1.25 or 5 mg/kg/day of NLX-112, they showed robust improvement of motor performance, with swimming latencies which were similar to those of WT mice. This effect of NLX-112 was maintained throughout the period of the study. ConclusionsThe improved motor function of SCA3 mice when treated with NLX-112 supports its investigation as a drug candidate for the treatment of ataxia and related movement disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/674027v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@f0a8e1org.highwire.dtl.DTLVardef@1df4d49org.highwire.dtl.DTLVardef@14af6a2org.highwire.dtl.DTLVardef@86096b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISpinocerebellar ataxia type 3 (SCA3) is marked by progressive motor disturbances C_LIO_LITargeting the serotonergic system is a promising strategy to treat SCA3 C_LIO_LITransgenic SCA3 mice were treated with NLX-112, a selective 5-HT1A agonist C_LIO_LIChronic NLX-112 normalized performance of mice in the motor swimming test C_LIO_LINLX-112 could constitute a drug candidate for treatment of the ataxia disorders C_LI

neuroscience↗

bioRxiv2025

Efficacy of chronic 5-HT1A receptor agonism by NLX-112 in a mouse model of Spinocerebellar Ataxia type 3

BackgroundSpinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by an elongated polyglutamine (polyQ) sequence in the ataxin-3 protein. This expansion triggers neuropathological events, leading to progressive motor disturbances. Currently, no approved therapy exists for this debilitating condition, but compelling evidence suggests that targeting the serotonergic system can significantly attenuate SCA3 disease progression in animal models. ObjectiveThis study aimed to assess the effects of NLX-112, a highly selective serotonin 1A receptor (5-HT1AR) full agonist, in the CMVMJD135 transgenic mouse model of SCA3. MethodsNLX-112 (0.625 and 5 mg/kg/day) and tandospirone (a 5-HT1AR partial agonist used as a comparator; 20 and 80 mg/kg/day) were administered chronically in drinking water for 34 weeks, starting prior to symptom onset. To evaluate the effects of the drugs on SCA3 mice, motor-related behavioral tests and neuropathological techniques were employed. ResultsTreatment with the higher dose of NLX-112 led to improvements in motor coordination and balance, and slowing of symptom deterioration as the disease progressed. These beneficial effects were not achieved with tandospirone. NLX-112 treatment also elicited neuroprotective effects, reducing dopaminergic (tyrosine hydroxylase-positive) cell loss and astrocyte reactivity in the substantia nigra. ConclusionsNLX-112 treatment, started pre-symptomatically, enhanced motor function, slowed disease progression and elicited neuroprotective effects in SCA3 mice, supporting its further development as a drug candidate for treatment of ataxia and related movement disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/671624v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@548b2corg.highwire.dtl.DTLVardef@7d2f51org.highwire.dtl.DTLVardef@ad8ee4org.highwire.dtl.DTLVardef@80213c_HPS_FORMAT_FIGEXP M_FIG C_FIG Key findingsO_LINLX-112 attenuated motor deficits of SCA3 mice, when administered chronically prior to disease onset. C_LIO_LINLX-112 reduced neuropathological biomarkers in SCA3 mice, namely by restoring dopaminergic neuron loss and decreasing astrocyte reactivity. C_LIO_LINLX-112 is a potential candidate for addressing ataxia-related deficits in SCA3 patients. C_LI

neuroscience↗

bioRxiv2025

Allosteric Modulation of Pathological Ataxin-3 Aggregation: A Path to Spinocerebellar Ataxia Type-3 Therapies

Spinocerebellar ataxia type 3 (SCA3) is a rare inherited neurodegenerative disease caused by the expansion of a polyglutamine repeat in the protease ataxin-3 (Atx3). Despite extensive knowledge of the downstream pathophysiology, no disease-modifying therapies are currently available to halt disease progression. The accumulation of protein inclusions enriched in the polyQ-expanded Atx3 in neurons suggests that inhibiting its self-assembly may yield targeted therapeutic approaches. Here it is shown that a supramolecular tweezer, CLR01, binds to a lysine residue on a positively charged surface patch of the Atx3 catalytic Josephin domain. At this site, the binding of CLR01 decreases the conformational fluctuations of the distal flexible hairpin. This results in reduced exposure of the nearby aggregation-prone region, which overlaps with the substrate ubiquitin binding site and primes Atx3 self-assembly, ultimately delaying Atx3 amyloid fibril formation and reducing the secondary nucleation rate, a process linked to fibril proliferation and toxicity. These effects translate into the reversal of synapse loss in a SCA3 cultured cortical neuron model, an improved locomotor function in a C. elegans SCA3 model, and a delay in disease onset, accompanied by reduced severity of motor symptoms in a SCA3 mouse model. This study provides critical insights into Atx3 self-assembly, revealing a novel allosteric site for designing CLR01-inspired therapies targeting pathological aggregation pathways while sparing essential functional sites. These findings emphasize that targeting allosteric sites in amyloid-forming proteins may offer unique opportunities to develop safe therapeutic strategies for various protein misfolding disorders.

biophysics↗