Biology subjects

Li, H. L.

Publications and source records attributed to Li, H. L..

6 recordsLinked to original sources

bioRxiv2025

PROX1 loss in adult mouse Schlemm's canal causes permanent ocular hypertension

Glaucoma is associated with ocular hypertension and lowering intraocular pressure is a key objective of glaucoma therapies. Recent studies have established a role for the Schlemms canal endothelium in this pressure increase and have shown it to have a unique, lymphatic-like, hybrid phenotype. However, the role of these lymphatic phenotypes in the adult canal remains uncertain. Long-term functional studies have been limited by systemic importance of lymphatic genes and lack of Schlemms canal-specific animal models. Here, we designed and validated a strategy using 4OH-tamoxifen-loaded nanocarriers to generate targeted, Schlemms canal specific knockout mice lacking lymphatic phenotypes. Using this system, we selectively deleted Prox1, the master transcription factor governing lymphatic fate. Within four weeks, intraocular pressure significantly increased, and ocular hypertension was maintained for at least 24 weeks. Unlike lymphatic vessels, which degenerate following Prox1 deletion, Schlemms canal reverted to a less functional vein-like phenotype with no change in size or morphology. These results highlight the utility of nanocarriers for tissue-specific genetic recombination and demonstrate that changes in lymphatic phenotypes alter intraocular pressure, providing new targets for glaucoma therapy. Moreover, as we found that PROX1 was downregulated with age in human Schlemms canal, these canal-specific conditional Prox1 knockout mice are a valuable new adult-onset model of ocular hypertension that captures key features of age-related human disease.

physiology↗

bioRxiv2023

LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology spread

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinsons disease (PD). These mutations elevate LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic target. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define. LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carrying LRRK2 mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of LRRK2 inhibitors efficacy against disease processes. We hypothesized that mutations in LRRK2 may not be directly related to a single disease pathway, but instead may elevate susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of -synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages. Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wildtype or LRRK2G2019S knock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3 to 6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 665 brain regions and subsequent linear diffusion modeling of progression. Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2G2019S mice that were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2G2019S mice, but had minimal effect in wildtype mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers, but additional work may be necessary to determine the potential effect in non-carriers. This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.

neuroscience↗

bioRxiv2022

Opposite regulation of glycogen metabolism by cAMP produced in the cytosol and at the plasma membrane

Cyclic AMP is produced in cells by two different types of adenylyl cyclases: at the plasma membrane by the transmembrane adenylyl cyclases (tmACs, ADCY1[~]ADCY9) and in the cytosol by the evolutionarily more conserved soluble adenylyl cyclase (sAC, ADCY10). By employing high-resolution extracellular flux analysis to study glycogen breakdown in real time, we show here thatcAMP regulates glycogen metabolism in opposite directions depending on its location of synthesis within cells. While the canonical tmAC-cAMP-PKA axis promotes glycogenolysis, we demonstrate that the non-canonical sAC-cAMP-Epac1 signalling suppresses glycogenolysis in a variety of cell types. Our findings demonstrate the importance of cAMP microdomain organization in glycogen metabolism and reveal a novel role of sAC in energy metabolism during glucose deprivation.

biochemistry↗

bioRxiv2020

Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation

Tau pathology is a diagnostic feature of Alzheimers disease (AD) but is also a prominent feature of Parkinsons disease (PD), including genetic forms of PD with mutations in leucine-rich repeat kinase 2 (LRRK2). In both diseases, tau pathology is progressive and correlates with cognitive decline. Neuropathological staging studies in humans and mouse models have suggested that tau spreads through the brain, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute to pathology spread. Further, it is unknown how mutations in the LRRK2 gene may modulate susceptibility to tau pathologys initiation or spread. In this study, we used seed-based models of tauopathy to capture spatiotemporal patterns of pathology in mice. Following the injection of AD brain-derived tau into the brains of non-transgenic mice, tau pathology spreads progressively through the brain in a spatiotemporal pattern that is well-explained by anatomical connectivity. We validated and compared network models based on diffusion along anatomical connections to predict tau spread, estimate regional vulnerability to tau pathology, and investigate gene expression patterns related to regional vulnerability. We further investigated tau pathology spread in mice harboring a mutation in LRRK2 and found that while tau pathology spread is still constrained by anatomical connectivity, it spreads preferentially in a retrograde direction to regions that are otherwise resilient in wildtype mice. This study provides a quantitative demonstration that tau pathology spreads along anatomical connections, explores the kinetics of this spread, and provides a platform for investigating the effect of genetic risk factors and treatments on the progression of tauopathies.

neuroscience↗

bioRxiv2020

Non-canonical regulation of glycogenolysis and the Warburg phenotype by soluble adenylyl cyclase

Cyclic AMP is produced in cells by two very different types of adenylyl cyclases: the canonical transmembrane adenylyl cyclases (tmACs, ADCY1[~]9) and the evolutionarily more conserved soluble adenylyl cyclase (sAC, ADCY10). While the role and regulation of tmACs is well documented, much less is known of sAC in cellular metabolism. We demonstrate here that sAC is an acute regulator of glycolysis, oxidative phosphorylation and glycogen metabolism, tuning their relative bioenergetic contributions. Suppression of sAC activity leads to aerobic glycolysis, enhanced glycogenolysis, decreased oxidative phosphorylation, and an elevated cytosolic NADH/NAD+ ratio, resembling the Warburg phenotype. Importantly, we found that glycogen metabolism is regulated in opposite directions by cAMP depending on its location of synthesis and downstream effectors. While the canonical tmAC-cAMP-PKA axis promotes glycogenolysis, we identify a novel sAC-cAMP-Epac1 axis that suppresses glycogenolysis. These data suggest that sAC is an autonomous bioenergetic sensor that suppresses aerobic glycolysis and glycogenolysis when ATP levels suffice. When the ATP level falls, diminished sAC activity induces glycogenolysis and aerobic glycolysis to maintain energy homeostasis.

biochemistry↗

bioRxiv2019

Energy efficient synaptic plasticity

Many aspects of the brains design can be understood as the result of evolutionary drive towards efficient use of metabolic energy. In addition to the energetic costs of neural computation and transmission, experimental evidence indicates that synaptic plasticity is metabolically demanding as well. As synaptic plasticity is crucial for learning, we examine how these metabolic costs enter in learning. We find that when synaptic plasticity rules are naively implemented, training neural networks requires extremely large amounts of energy when storing many patterns. We propose that this is avoided by precisely balancing labile forms of synaptic plasticity with more stable forms. This algorithm, termed synaptic caching, boosts energy efficiency manifold. Our results yield a novel interpretation of the multiple forms of neural synaptic plasticity observed experimentally, including synaptic tagging and capture phenomena. Furthermore our results are relevant for energy efficient neuromorphic designs.

neuroscience↗