Liping Liu

All Publications

• Perivascular neurons instruct 3D vascular lattice formation via neurovascular contact. Cell Toma, K., Zhao, M., Zhang, S., Wang, F., Graham, H. K., Zou, J., Modgil, S., Shang, W. H., Tsai, N. Y., Cai, Z., Liu, L., Hong, G., Kriegstein, A. R., Hu, Y., Körbelin, J., Zhang, R., Liao, Y. J., Kim, T. N., Ye, X., Duan, X. 2024

  Abstract

  The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet. Developmental ablation of Fam19a4/Nts-RGCs led to disoriented growth of penetrating vessels near the ganglion cell layer (GCL), leading to a disorganized 3D vascular lattice. We identified enriched PIEZO2 expression in Fam19a4/Nts-RGCs. Piezo2 loss from all retinal neurons or Fam19a4/Nts-RGCs abolished the direct neurovascular contacts and phenocopied the Fam19a4/Nts-RGC ablation deficits. The defective vascular structure led to reduced capillary perfusion and sensitized the retina to ischemic insults. Furthermore, we uncovered a Piezo2-dependent perivascular granule cell subset for cerebellar vascular patterning, indicating neuronal Piezo2-dependent 3D vascular patterning in the brain.

  View details for DOI 10.1016/j.cell.2024.04.010

  View details for PubMedID 38733989

• 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

• 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