Dong Liu

All Publications

• Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration. bioRxiv : the preprint server for biology Liu, D., Webber, H. C., Bian, F., Xu, Y., Prakash, M., Feng, X., Yang, M., Yang, H., You, I., Li, L., Liu, L., Liu, P., Huang, H., Chang, C., Liu, L., Shah, S. H., Torre, A. L., Welsbie, D. S., Sun, Y., Duan, X., Goldberg, J. L., Braun, M., Lansky, Z., Hu, Y. 2024

  Abstract

  Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We found that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a striking decrease of axonal mitochondria. Surprisingly, we discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Encouragingly, overexpressing OPTN/TRAK1/KIF5B reverses not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes striking ON regeneration. Therefore, in addition to generating new animal models for NTG and ALS, our results establish OPTN as a novel facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.

  View details for DOI 10.1101/2024.04.02.587832

  View details for PubMedID 38617277

• Circadian Disruption across Lifespan Impairs Glucose Homeostasis and Insulin Sensitivity in Adult Mice. Metabolites Her, T. K., Li, J., Lin, H., Liu, D., Root, K. M., Regal, J. F., Alejandro, E. U., Cao, R. 2024; 14 (2)

  Abstract

  Circadian rhythm disruption is associated with impaired glucose homeostasis and type 2 diabetes. For example, night shift work is associated with an increased risk of gestational diabetes. However, the effects of chronic circadian disruption since early life on adult metabolic health trajectory remain unknown. Here, using the "Short Day" (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was used to disrupt mouse circadian rhythms across the lifespan, we investigated glucose homeostasis in adult mice. Adult SD mice were fully entrained into the 8 h/8 h LD cycle, and control mice were entrained into the 12 h/12 h LD cycle. Under a normal chow diet, female and male SD mice displayed a normal body weight trajectory. However, female but not male SD mice under a normal chow diet displayed glucose intolerance and insulin resistance, which are associated with impaired insulin signaling/AKT in the skeletal muscle and liver. Under high-fat diet (HFD) challenges, male but not female SD mice demonstrated increased body weight gain compared to controls. Both male and female SD mice developed glucose intolerance under HFD. Taken together, these results demonstrate that environmental disruption of circadian rhythms contributes to obesity in a sexually dimorphic manner but increases the risk of glucose intolerance and insulin resistance in both males and females.

  View details for DOI 10.3390/metabo14020126

  View details for PubMedID 38393018

• Differential effects of SARM1 inhibition in traumatic glaucoma and EAE optic neuropathies. Molecular therapy. Nucleic acids Liu, P., Chen, W., Jiang, H., Huang, H., Liu, L., Fang, F., Li, L., Feng, X., Liu, D., Dalal, R., Sun, Y., Jafar-Nejad, P., Ling, K., Rigo, F., Ye, J., Hu, Y. 2023; 32: 13-27

  Abstract

  Optic neuropathy is a group of optic nerve (ON) diseases withprogressive degeneration of ON and retinal ganglion cells(RGCs). The lack of neuroprotective treatments is a central challenge for this leading cause of irreversible blindness. SARM1 (sterile alpha and TIR motif-containing protein 1) has intrinsic nicotinamide adenine dinucleotide (NAD+) hydrolase activity that causes axon degeneration by degrading axonal NAD+ significantly after activation by axon injury. SARM1 deletion is neuroprotective in many, but not all, neurodegenerative disease models. Here, we compare two therapy strategies for SARM1 inhibition, antisense oligonucleotide (ASO) and CRISPR, with germline SARM1 deletion in the neuroprotection of three optic neuropathy mouse models. This study reveals that, similar to germline SARM1 knockout in every cell, local retinal SARM1 ASO delivery and adeno-associated virus (AAV)-mediated RGC-specific CRISPR knockdown of SARM1 provide comparable neuroprotection to both RGC somata and axons in the silicone oil-induced ocular hypertension (SOHU) glaucoma model but only protect RGC axons, not somata, after traumatic ON injury. Surprisingly, neither of these two therapy strategies of SARM1 inhibition nor SARM1 germline knockout (KO) benefits RGC or ON survival in the experimental autoimmune encephalomyelitis (EAE)/optic neuritis model. Our studies therefore suggest that SARM1 inhibition by local ASO delivery or AAV-mediated CRISPR is a promising neuroprotective gene therapy strategy for traumatic and glaucomatous optic neuropathies but not for demyelinating optic neuritis.

  View details for DOI 10.1016/j.omtn.2023.02.029

  View details for PubMedID 36950280

• Maprotiline restores ER homeostasis and rescues neurodegeneration via Histamine Receptor H1 inhibition in retinal ganglion cells. Nature communications Chen, W., Liu, P., Liu, D., Huang, H., Feng, X., Fang, F., Li, L., Wu, J., Liu, L., Solow-Cordero, D. E., Hu, Y. 2022; 13 (1): 6796

  Abstract

  When the protein or calcium homeostasis of the endoplasmic reticulum (ER) is adversely altered, cells experience ER stress that leads to various diseases including neurodegeneration. Genetic deletion of an ER stress downstream effector, CHOP, significantly protects neuron somata and axons. Here we report that three tricyclic compounds identified through a small-scale high throughput screening using a CHOP promoter-driven luciferase cell-based assay, effectively inhibit ER stress by antagonizing their common target, histamine receptor H1 (HRH1). We further demonstrated that systemic administration of one of these compounds, maprotiline, or CRISPR-mediated retinal ganglion cell (RGC)-specific HRH1 inhibition, delivers considerable neuroprotection of both RGC somata and axons and preservation of visual function in two mouse optic neuropathy models. Finally, we determine that maprotiline restores ER homeostasis by inhibiting HRH1-mediated Ca2+ release from ER. In this work we establish maprotiline as a candidate neuroprotectant and HRH1 as a potential therapeutic target for glaucoma.

  View details for DOI 10.1038/s41467-022-34682-y

  View details for PubMedID 36357388

• Neuroprotection of SARM1 Inhibition in Traumatic and Glaucomatous but not in EAE Optic Neuropathies Liu, P., Huang, H., Chen, W., Fang, F., Li, L., Feng, X., Liu, L., Liu, D., Dalal, R., Sun, Y., Ling, K., Rigo, F., Hu, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022

  View details for Web of Science ID 000844401303121

• NMNAT2 and NAD(+) are Downregulated in Glaucomatous RGCs and Overexpression of NMNAT2 Rescues Glaucomatous Neurodegeneration Liu, D., Fang, F., Zhuang, P., Feng, X., Liu, P., Huang, H., Li, L., Chen, W., Liu, L., Sun, Y., Jiang, H., Ye, J., Hu, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022

  View details for Web of Science ID 000844401303120

• Autistic-like behavior and cerebellar dysfunction in <i>Bmal1</i> mutant mice ameliorated by mTORC1 inhibition MOLECULAR PSYCHIATRY Liu, D., Nanclares, C., Simbriger, K., Fang, K., Lorsung, E., Le, N., Amorim, I., Chalkiadaki, K., Pathak, S., Li, J., Gewirtz, J. C., Jin, V. X., Kofuji, P., Araque, A., Orr, H. T., Gkogkas, C. G., Cao, R. 2023; 28 (9): 3727-3738

  Abstract

  Although circadian and sleep disorders are frequently associated with autism spectrum disorders (ASD), it remains elusive whether clock gene disruption can lead to autistic-like phenotypes in animals. The essential clock gene Bmal1 has been associated with human sociability and its missense mutations are identified in ASD. Here we report that global Bmal1 deletion led to significant social impairments, excessive stereotyped and repetitive behaviors, as well as motor learning disabilities in mice, all of which resemble core behavioral deficits in ASD. Furthermore, aberrant cell density and immature morphology of dendritic spines were identified in the cerebellar Purkinje cells (PCs) of Bmal1 knockout (KO) mice. Electrophysiological recordings uncovered enhanced excitatory and inhibitory synaptic transmission and reduced firing rates in the PCs of Bmal1 KO mice. Differential expression of ASD- and ataxia-associated genes (Ntng2, Mfrp, Nr4a2, Thbs1, Atxn1, and Atxn3) and dysregulated pathways of translational control, including hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling, were identified in the cerebellum of Bmal1 KO mice. Interestingly, the antidiabetic drug metformin reversed mTORC1 hyperactivation and alleviated major behavioral and PC deficits in Bmal1 KO mice. Importantly, conditional Bmal1 deletion only in cerebellar PCs was sufficient to recapitulate autistic-like behavioral and cellular changes akin to those identified in Bmal1 KO mice. Together, these results unveil a previously unidentified role for Bmal1 disruption in cerebellar dysfunction and autistic-like behaviors. Our findings provide experimental evidence supporting a putative role for dysregulation of circadian clock gene expression in the pathogenesis of ASD.

  View details for DOI 10.1038/s41380-022-01499-6

  View details for Web of Science ID 000770195800001

  View details for PubMedID 35301425

  View details for PubMedCentralID PMC9481983

• NMNAT2 Is Downregulated in Glaucomatous RGCs and RGC-Specific Gene Therapy Rescues Neurodegeneration and Visual Function. Molecular therapy : the journal of the American Society of Gene Therapy Fang, F., Zhuang, P., Feng, X., Liu, P., Liu, D., Huang, H., Li, L., Chen, W., Liu, L., Sun, Y., Jiang, H., Ye, J., Hu, Y. 1800

  Abstract

  The lack of neuroprotective treatments for retinal ganglion cells (RGCs) and optic nerve (ON) is a central challenge for glaucoma management. Emerging evidence suggests that redox factor NAD+ decline is a hallmark of aging and neurodegenerative diseases. Supplementation with NAD+ precursors and overexpression of NMNAT1, the key enzyme in the NAD+ biosynthetic process, have significant neuroprotective effects. We first profile the translatomes of RGCs in naive mice and mice with silicone oil-induced ocular hypertension (SOHU)/glaucoma by RiboTag mRNA sequencing. Intriguingly, only NMNAT2, but not NMNAT1 or NMNAT3, is significantly decreased in SOHU glaucomatous RGCs, which we confirm by in situ hybridization. We next demonstrate that AAV2 intravitreal injection-mediated overexpression of long half-life NMNAT2 mutant driven by RGC-specific mouse gamma-synuclein (mSncg) promoter restores decreased NAD+ levels in glaucomatous RGCs and ONs. Moreover, this RGC-specific gene therapy strategy delivers significant neuroprotection of both RGC soma and axon and preservation of visual function in the traumatic ON crush model and the SOHU glaucoma model. Collectively, our studies suggest that the weakening of NMNAT2 expression in glaucomatous RGCs contributes to a deleterious NAD+ decline and that modulating RGC intrinsic NMNAT2 levels by AAV2-mSncg vector is a promising gene therapy for glaucomatous neurodegeneration.

  View details for DOI 10.1016/j.ymthe.2022.01.035

  View details for PubMedID 35114390

• mTOR signaling regulates central and peripheral circadian clock function PLOS GENETICS Ramanathan, C., Kathale, N. D., Liu, D., Lee, C., Freeman, D. A., Hogenesch, J. B., Cao, R., Liu, A. C. 2018; 14 (5): e1007369

  Abstract

  The circadian clock coordinates physiology and metabolism. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of tissues and cells including the SCN, here we continued to investigate the role of mTOR in orchestrating autonomous clock functions in central and peripheral circadian oscillators. Using a combination of genetic and pharmacological approaches we show that mTOR regulates intrinsic clock properties including period and amplitude. In peripheral clock models of hepatocytes and adipocytes, mTOR inhibition lengthens period and dampens amplitude, whereas mTOR activation shortens period and augments amplitude. Constitutive activation of mTOR in Tsc2-/-fibroblasts elevates levels of core clock proteins, including CRY1, BMAL1 and CLOCK. Serum stimulation induces CRY1 upregulation in fibroblasts in an mTOR-dependent but Bmal1- and Period-independent manner. Consistent with results from cellular clock models, mTOR perturbation also regulates period and amplitude in the ex vivo SCN and liver clocks. Further, mTOR heterozygous mice show lengthened circadian period of locomotor activity in both constant darkness and constant light. Together, these results support a significant role for mTOR in circadian timekeeping and in linking metabolic states to circadian clock functions.

  View details for DOI 10.1371/journal.pgen.1007369

  View details for Web of Science ID 000434016500019

  View details for PubMedID 29750810

  View details for PubMedCentralID PMC5965903