Biology subjects

Velazquez, R.

Publications and source records attributed to Velazquez, R..

11 recordsLinked to original sources

bioRxiv2026

Ringer Loss in Uncovers Mitochondrial Complex I Deficits Characteristic of Human Parkinson's Disease

Tubulin polymerization promoting proteins (TPPPs) are known for their cytoskeletal regulation across species; however, emerging evidence suggests broader cellular functions, including potential roles in mitochondrial biology. Here, we identify the Drosophila homolog of human TPPP, Ringer, as a previously unrecognized regulator of mitochondrial bioenergetics and electron transport chain complex I (CI) function. Ringer is enriched in the mitochondrial matrix, and its loss results in reduced levels of multiple CI subunits and assembly factors and a significant decrease in CI enzymatic activity. Notably, similar deficits are observed in postmortem human Parkinsons disease (PD) brain tissues, underscoring the translational relevance of our Drosophila model and highlighting conserved, disease-associated mechanisms. Pharmacological administration of the CI-specific reactive oxygen species (ROS) scavenger, resveratrol, ameliorates superoxide levels and improves CI enzymatic activity and ATP production in ringer mutants, demonstrating that targeted antioxidant therapeutics can improve bioenergetic function with Ringer loss. Together, these findings establish Ringer as a key regulator of mitochondrial bioenergetics and reveal CI instability as a potential mechanism underlying PD-associated mitochondrial dysfunction, providing a robust and translationally meaningful framework for future therapeutic exploration.

neuroscience↗

bioRxiv2026

Dyrk1a inhibition with the Novel Compound DYR533: A Cross-Disease Therapeutic Strategy Targeting Amyloidosis, Tau Pathogenesis, and Neuroinflammation

Alzheimers disease (AD) and related dementias are rapidly increasing in prevalence, yet disease-modifying therapies remain largely focused on amyloid-{beta} (A{beta}) with limited efficacy against tau pathology and neuroinflammation--key drivers of neurodegeneration and clinical decline. Dual-specificity tyrosine-phosphorylation-regulated kinase 1a (Dyrk1a) phosphorylates tau and amyloid precursor protein and regulates inflammatory signaling, positioning it as a convergence point across pathogenic pathways. We show that brain Dyrk1a protein levels are consistently elevated across ADRDs, replicating findings in AD, confirming prior observations in Picks disease, and demonstrating dysregulation in corticobasal degeneration and progressive supranuclear palsy. We developed DYR533, a selective, orally bioavailable, brain-penetrant Type 1 Dyrk1a kinase inhibitor that also inhibits autophosphorylation and reduces kinase abundance. Across three mouse models (3xTg-AD, PS19, Ts65Dn), DYR533 reduced pathological tau hyperphosphorylation, attenuated neuroinflammation, ameliorated amyloidosis, and improved anxiety-like behavior and spatial memory, collectively supporting Dyrk1a inhibition and DYR533 as a therapeutic strategy for ADRD.

neuroscience↗

bioRxiv2026

Protocol for using an ELISA assay to detect total α-synuclein levels in Drosophila melanogaster lines expressing human α-synuclein point mutations

In Parkinsons disease (PD), aggregation of alpha-synuclein (-syn) contributes to neuronal dysfunction and death, particularly in dopaminergic neurons, driving disease progression. Several pathogenic point mutations have been identified in human -syn such as A30P, E46K, H50Q, G51D, A53T and A53E that have been associated with PD. In this study, a sandwich ELISA assay was developed to quantify total -syn levels in various Drosophila melanogaster genotypes expressing A30P, E46K, G51D and A53T. Using this approach, we compared -syn levels across wild-type (WT) and mutant forms of the protein. The E46K and A53T mutations exhibited higher total -syn concentrations compared to WT and the G51D mutation. In addition to characterizing mutationdependent differences in -syn levels, this assay was applied to evaluate smallmolecule modulators that inhibit -syn aggregation. These findings demonstrate that the ELISA-based approach provides a useful platform for quantifying -syn and assessing potential therapeutic compounds targeting syn pathology.

neuroscience↗

bioRxiv2025

Sex-Specific Links Between Low Choline, Metabolic Dysfunction, andNeuropathology in Obesity: Insights from Humans and the 3xTg-AD MouseModel of Alzheimer's disease.

The growing prevalence of obesity, a risk factor for disorders such as Alzheimers Disease (AD), raises concerns about the effects on cognitive health. AD currently impacts 6.9 million Americans aged 65 and older and is characterized by the presence of amyloid beta (A{beta}) plaques, neurofibrillary tau tangles, and neuroinflammation, all of which contribute to cognitive impairment. Insulin resistance, common in both obesity and AD, disrupts brain glucose metabolism and accelerates neurodegeneration. Understanding the factors that link these conditions could lead to new strategies for combating disease. Notably, the B-like vitamin choline is necessary for fat metabolism and has been shown to help reduce obesity incidence. However, [~]90% of Americans are deficient, and decreases in this nutrient have been associated with cognitive decline. Here, we examined circulating choline levels, inflammation, and metabolic dysfunction in human participants with obesity (BMI > 30) compared to normal BMIs (18.5-24.9), as well as in 3xTg-AD mice, an AD model, fed a choline-deficient diet throughout adulthood. Our results revealed that obese participants exhibited significantly lower circulating choline levels compared to those with a healthy BMI. Lower choline levels correlated with higher %Body fat and increased markers of insulin resistance. Elevated inflammatory cytokines in obese participants were also seen in 3xTg-AD mice on a choline-deficient diet, which exhibited significant weight gain and metabolic dysfunction. AD-like pathology was also exacerbated in choline deficient 3xTg-AD mice. These findings underscore the relationship between low choline levels, obesity, insulin resistance, and cognitive decline risk. Adequate choline intake may mitigate the risk of obesity, potentially preventing cognitive decline and associated diseases. HighlightsO_LIObesity is linked to increased insulin resistance (IR) and systemic inflammation, both of which are recognized risk factors for Alzheimers disease (AD). C_LIO_LIWomen exhibit lower circulating choline levels compared to men, and obese individuals display significantly lower choline levels than those with a healthy BMI. C_LIO_LILower circulating choline levels are linked to a higher body fat percentage, increased markers of IR and liver dysfunction, as well as heightened systemic inflammation. C_LIO_LI3xTg-AD mice on a choline-deficient diet experience considerable weight gain, metabolic dysfunction, heightened systemic inflammation, and AD-like pathology, resembling the conditions observed in obese human participants. C_LI

pathology↗

bioRxiv2024

Adult choline supplementation in a Down syndrome model reduces co-morbidities and improves cognition

Down syndrome (DS) is the most common cause of early-onset Alzheimers disease (AD). Dietary choline has been proposed as a modifiable factor to improve cognitive and pathological outcomes of AD, especially as many do not reach adequate daily intake levels. Perinatal choline supplementation (Ch+) in the Ts65Dn mouse model of DS protects offspring against AD-relevant pathology and improves cognition, and dietary Ch+ in adult AD models also ameliorates pathology and improves cognition. However, dietary Ch+ in adult Ts65Dn mice has not yet been explored. To test whether Ch+ in adulthood improves DS co-morbidities, we fed trisomic Ts65Dn mice and disomic littermate controls with either choline normal (ChN; 1.1 g/kg) or Ch+ (5 g/kg) diets from 4.5-14 months of age. We found that Ch+ improved cognitive flexibility in a reverse place preference task and reduced weight gain and peripheral inflammation in female mice, whereas Ch+ improved glucose metabolism in male mice. In conclusion, we found that adulthood Ch+ benefits behavioral and biological factors important for general well-being in DS and related to AD risk.

neuroscience↗

bioRxiv2024

A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor specificity

P-cadherin (pCAD) and LI-cadherin (CDH17) are cell surface proteins belonging to the cadherin superfamily that are both highly expressed in colorectal cancer. This co-expression profile presents a novel and attractive opportunity for a dual targeting approach using an antibody-drug conjugate (ADC). In this study, we used a unique avidity-driven in vitro screening approach to generate pCAD x CDH17 bispecific antibodies that selectively targets cells expressing both antigens over cells expressing only pCAD or only CDH17. Based off the in vitro results we selected a lead bispecific antibody to link to the cytotoxic payload MMAE to generate a pCAD x CDH17 bispecific MMAE ADC. In in vivo dual flank mouse models, we demonstrated antitumor activity of the bispecific ADC in tumors expressing both antigens, but not in tumors expressing only pCAD or only CDH17. Overall, the preclinical data presented here suggests that a pCAD x CDH17 bispecific MMAE ADC has the potential to provide clinical benefit to colorectal cancer patients.

cancer biology↗

bioRxiv2023

Reduced PIN1 gene expression in neocortical and limbic brain regions in female Alzheimer's patients correlates with cognitive and neuropathological phenotypes

Women have a higher incidence of Alzheimers disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify the molecular networks that underpin the sex-associated risk of AD. Recent efforts have identified PIN1 as a key regulator of tau phosphorylation signaling pathway. Pin1 is the only gene, to date, that when deleted can cause both tau and A{beta}-related pathologies in an age-dependent manner. We analyzed multiple brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels, in an aging and AD cohort, which revealed reduced PIN1 levels driven by females. Then, we validated this observation in an independent dataset (ROS/MAP) which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function, in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again, driven predominantly by female subjects. Our results show that while both male and female AD patients show decreased PIN1 expression, changes occur before the onset of clinical symptoms of AD in females and correlate to early events associated with AD risk (e.g., synaptic dysfunction). These changes are specific to neurons, and may be a potential prognostic marker to assess AD risk in the aging population and even more so in AD females with increased risk of AD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/553279v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@95bd4eorg.highwire.dtl.DTLVardef@bf4e3corg.highwire.dtl.DTLVardef@1a9468corg.highwire.dtl.DTLVardef@56c15e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Low circulating choline, a modifiable dietary factor, is associated with the pathological progression and metabolome dysfunction in Alzheimers disease.

Most Americans ([~]90%) are deficient in dietary choline, an essential nutrient. Associations between circulating choline and pathological progression in Alzheimers disease (AD) remain unknown. Here, we examined these associations and performed a metabolomic analysis in blood serum from severe AD, moderate AD, and healthy controls. Additionally, to gain mechanistic insight, we assessed the effects of dietary choline deficiency (Ch-) in 3xTg-AD mice and choline supplementation (Ch+) in APP/PS1 mice. In humans, we found AD-associated reductions in choline, its derivative acetylcholine (ACh), and elevated pro-inflammatory cytokine TNF. Choline and ACh were negatively correlated with Plaque density, Braak stage, and TNF, but positively correlated with MMSE and brain weight. Metabolites L-Valine, 4-Hydroxyphenylpyruvic, Methylmalonic, and Ferulic acids were associated with choline levels. In mice, Ch-paralleled AD severe, but Ch+ was protective. In conclusion, low circulating choline is associated with AD-neuropathological progression, illustrating the importance of dietary choline consumption to offset disease.

pathology↗

bioRxiv2022

Dietary choline intake is necessary to prevent systems-wide organ pathology and reduce Alzheimers disease hallmarks

Evidence suggests that environmental factors may contribute to Alzheimers disease (AD). The B-like vitamin choline plays key roles in body- and brain-related functions. Choline produced endogenously by the phosphatidylethanolamine N-methyltransferase (PEMT) enzyme in the liver is not sufficient for adequate physiological functions, necessitating daily dietary intake. [~]90% of Americans dont reach the recommended daily choline intake. Thus, its imperative to determine whether dietary deficiency increases disease outcomes. Here, we placed 3xTg-AD, a model of AD, and non-transgenic (NonTg) control mice on either a sufficient choline (ChN) or choline deficient (Ch-; choline deficiency) diet from 3 to 12 (early to late adulthood) months of age. Ch- reduced plasma choline and acetylcholine levels, increased weight, and impaired both glucose metabolism and motor function in NonTg, with 3xTg-AD mice showing greater deficits. Tissue analyses showed cardiac and liver pathology, and elevated Amyloid-{beta} and phosphorylated tau in the hippocampus and cortex of 3xTg-AD Ch- mice. Unbiased proteomic analyses revealed Ch- altered hippocampal networks associated with microtubule function and postsynaptic membrane regulation. In plasma, Ch- altered protein networks associated with insulin metabolism, mitochondrial function, and inflammation. Collectively, our data highlight that dietary choline intake is necessary to prevent systems-wide organ pathology and reduce AD hallmark pathologies.

neuroscience↗

bioRxiv2022

Human HspB1, HspB3, HspB5 and HspB8: Shaping these Disease Factors during Vertebrate Evolution

Small heat shock proteins (sHSPs) emerged early in evolution and occur in all domains of life and nearly in all species, including humans. Mutations in four sHSPs (HspB1, HspB3, HspB5, HspB8) are associated with neuromuscular disorders. The aim of this study is to investigate the evolutionary forces shaping these sHSPs during vertebrate evolution. We performed comparative evolutionary analyses on a set of orthologous sHSP sequences, based on the ratio of non-synonymous: synonymous substitution rates for each codon. We found that these sHSPs had been historically exposed to different degrees of purifying selection, decreasing in this order: HspB8 > HspB1, HspB5 > HspB3. Within each sHSP, regions with different degrees of purifying selection can be discerned, resulting in characteristic selective pressure profiles. The conserved -crystallin domains were exposed to the most stringent purifying selection compared to the flanking regions, supporting a dimorphic pattern of evolution. Thus, during vertebrate evolution the different sequence partitions were exposed to different and measurable degrees of selective pressures. Among the disease-associated mutations, most are missense mutations primarily in HspB1 and to a minor extent in the other sHSPs. Our data provide an explanation for this disparate incidence. Contrary to the expectation, most missense mutations cause dominant disease phenotypes. Theoretical considerations support a connection between the historic exposure of these sHSP genes to a high degree of purifying selection and the unusual prevalence of genetic dominance of the associated disease phenotypes. Our study puts the genetics of inheritable sHSP-borne diseases into the context of vertebrate evolution.

evolutionary biology↗

bioRxiv2020

Biomarker-guided treatment strategies for ovarian cancer identified from a heterogeneous panel of patient-derived tumor xenografts

Advanced ovarian cancers are a leading cause of cancer-related death in women. Such cancers are currently treated with surgery and chemotherapy which is often temporarily successful but exhibits a high rate of relapse after which treatment options are few. Here we assess the responses of a panel of patient-derived ovarian cancer xenografts (PDXs) to 19 mono and combination therapies, including small molecules and antibody-drug conjugates. The PDX panel aimed to mimic the heterogeneity of disease observed in patients, and exhibited a distribution of responsiveness to standard of care chemotherapy similar to human clinical data. Three monotherapies and one drug combination were found to be active in different subsets of PDXs. By analyzing gene expression data we identified gene expression biomarkers predictive of responsiveness to each of three novel targeted therapy regimens. While no single treatment had as high a response rate as chemotherapy, nearly 90% of PDXs were eligible for and responded to at least one biomarker-guided treatment, including tumors resistant to standard chemotherapy. Biomarker frequency was similar in human patients, suggesting the possibility of a new therapeutic approach to ovarian cancer and demonstrating the potential power of PDX-based trials in broadening the reach of precision cancer medicine.

cancer biology↗