Biology subjects

Mar, A. C.

Publications and source records attributed to Mar, A. C..

5 recordsLinked to original sources

bioRxiv2025

Myelin pathology is a key feature of X-linked Dystonia Parkinsonism

X-linked Dystonia-Parkinsonism (XDP) is a progressive, adult-onset neurodegenerative movement disorder that predominantly affects males of Filipino descent1-3. The disease is caused by the insertion of a SINE-VNTR-Alu subfamily F (SVA_F) retrotransposon within an intron of the TATA-box binding protein-associated factor 1 (TAF1) gene4. A major barrier to understanding the pathophysiology of XDP has been the lack of relevant animal models. Here, we introduce a novel conditional humanized XDP mouse model harboring a hybrid mouse-human Taf1/TAF1 gene (hyTAF1) containing the pathogenic SVA_F insertion. We activated the hyTAF1 in Nestin+ neural progenitor cells and found that the resulting XDP male mice recapitulate features of the human disease including severe motor impairment, striatal atrophy, and reactive gliosis. Transcriptomic, histological, and electron microscopy analysis revealed a dramatic reduction in oligodendrocyte lineage cells and widespread myelin disruption. Consistent with these findings, postmortem brain tissue from XDP patients revealed similar myelin pathology, including near-complete loss of myelin in parts of the medial prefrontal cortex. Together, these results identify oligodendrocyte dysfunction and myelin loss as previously unrecognized contributors to XDP pathogenesis, providing new mechanistic insight into this debilitating disorder.

neuroscience↗

bioRxiv2025

Single-Domain Antibody-Based Autophagosome-Targeting Chimera for Tau Clearance and Motor Function Restoration in Tauopathies

Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge. Here, we present 1D9-LIR{Delta}TP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance via the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIR{Delta}TP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In frontotemporal dementia (FTD) patient-derived neurons and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIR{Delta}TP53INP2 significantly reduced tau levels and improved motor function in mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis

Structured abstractO_ST_ABSINTRODUCTIONC_ST_ABSDisturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimers disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes. METHODSWe employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo MRI, to investigate early capillary dysfunction in Tg-SwDI mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances. RESULTSOur study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and Amyloid-{beta} (A{beta}) load in 9-10-month-old Tg-SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced A{beta} load. DISCUSSIONThese findings underscore the importance of capillary flow disturbances as early biomarkers in presymptomatic AD and highlight the potential of CAIs for preserving vascular integrity in the early stages of AD.

neuroscience↗

bioRxiv2024

Unraveling cysteine deficiency-associated rapid weight loss

Forty percent of the US population and 1 in 6 individuals worldwide are obese, and the incidence of this disease is surging globally1,2. Various dietary interventions, including carbohydrate and fat restriction, and more recently amino acid restriction, have been explored to combat this epidemic3-6. We sought to investigate the impact of removing individual amino acids on the weight profiles of mice. Compared to essential amino acid restriction, induction of conditional cysteine restriction resulted in the most dramatic weight loss, amounting to 20% within 3 days and 30% within one week, which was readily reversed. This weight loss occurred despite the presence of substantial cysteine reserves stored in glutathione (GSH) across various tissues7. Further analysis demonstrated that the weight reduction primarily stemmed from an increase in the utilization of fat mass, while locomotion, circadian rhythm and histological appearance of multiple other tissues remained largely unaffected. Cysteine deficiency activated the integrated stress response (ISR) and NRF2-mediated oxidative stress response (OSR), which amplify each other, leading to the induction of GDF15 and FGF21, hormones associated with increased lipolysis, energy homeostasis and food aversion8-10. We additionally observed rapid tissue coenzyme A (CoA) depletion, resulting in energetically inefficient anaerobic glycolysis and TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, -ketoglutarate, nitrogen rich compounds and amino acids. In summary, our investigation highlights that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism, and stress signaling compared to other amino acid restrictions. These findings may pave the way for innovative strategies for addressing a range of metabolic diseases and the growing obesity crisis.

physiology↗

bioRxiv2022

A dedicated hypothalamic oxytocin circuit controls aversive social learning

To survive and thrive in a complex social group, it is essential to not only know who to approach but more importantly who to avoid. After a single defeat, mice learn to stay away from the winning aggressor for weeks. Here, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin receptor expressing cells in the anterior subdivision of ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance learning. After defeat, aVMHvlOXTR cells drastically increase their responses to aggressor cues. This response change is functionally important as optogenetic activation of aVMHvlOXTR cells elicits time-locked social avoidance towards a benign social target whereas inactivating the cells suppresses defeat-induced social avoidance. Furthermore, OXTR in the aVMHvl is itself essential for the behavior change. Knocking out OXTR in the aVMHvl or antagonizing the receptor during defeat, but not during post-defeat social interaction, impairs defeat-induced social avoidance. aVMHvlOXTR receives its private source of oxytocin from SOROXT cells, which are highly activated by the noxious somatosensory inputs associated with defeat. Oxytocin released from SOROXT depolarizes aVMHvlOXTR cells and facilitates their synaptic potentiation, and hence, increases aVMHvlOXTR cell responses to aggressor cues. Ablating SOROXT cells impairs defeat-induced social avoidance learning whereas activating the cells promotes social avoidance after a subthreshold defeat experience. Altogether, our study reveals an essential role of SOROXT-aVMHvlOXTR circuit in defeat-induced social learning and highlights the importance of brain oxytocin system in social plasticity.

neuroscience↗