About

Nien-Pei Tsai, Ph.D., is the Principal Investigator at the Tsai Lab at UIUC, specializing in molecular and cellular neurobiology. His research focuses on understanding the mechanisms underlying neural function and neurobiological processes. As a senior researcher, he leads investigations into neurobiological systems, contributing to the broader scientific understanding of neural mechanisms.

Research topics

• Biology
• Neuroscience
• Genetics
• Medicine
• Cell biology
• Psychiatry
• Bioinformatics

Selected publications

• Reviewer #1 (Public review): Modulating inter-mitochondrial contacts to increase membrane potential for mitigating blue light damage

  2026-04-20

  peer-reviewOpen access

  Mitochondrial membrane potential (MMP) is essential for mitochondrial functions, yet current methods for modulating MMP lack precise spatial and temporal control. Here, we present an optogenetic system that enables reversible formation of inter-mitochondrial contacts (mito-contacts) with high spatiotemporal precision. Blue light stimulation induces rapid formation of mito-contacts, which fully dissipate upon cessation of illumination. These light-induced mito-contacts can enhance MMP, leading to increased ATP production under stress conditions. Moreover, in human retinal cells and C. elegans, high MMP induced by mito-contacts alleviates the deleterious effects of prolonged blue light exposure, restoring energy metabolism and extending organismal lifespan. This optogenetic approach provides a powerful tool for modulating MMP and offers potential therapeutic applications for diseases linked to mitochondrial dysfunction.

  PublisherDOI

• Reviewer #2 (Public review): Modulating inter-mitochondrial contacts to increase membrane potential for mitigating blue light damage

  2026-04-20

  peer-reviewOpen access

  Mitochondrial membrane potential (MMP) is essential for mitochondrial functions, yet current methods for modulating MMP lack precise spatial and temporal control. Here, we present an optogenetic system that enables reversible formation of inter-mitochondrial contacts (mito-contacts) with high spatiotemporal precision. Blue light stimulation induces rapid formation of mito-contacts, which fully dissipate upon cessation of illumination. These light-induced mito-contacts can enhance MMP, leading to increased ATP production under stress conditions. Moreover, in human retinal cells and C. elegans, high MMP induced by mito-contacts alleviates the deleterious effects of prolonged blue light exposure, restoring energy metabolism and extending organismal lifespan. This optogenetic approach provides a powerful tool for modulating MMP and offers potential therapeutic applications for diseases linked to mitochondrial dysfunction.

  PublisherDOI

• <scp>E3</scp> Ubiquitin Ligase Nedd4‐2 Exacerbates Seizure‐Induced Mitochondrial Defects in an Alzheimer's Disease Mouse Model

  Journal of Neurochemistry · 2026-04-01

  articleOpen accessSenior authorCorresponding

  Seizure is one of the common comorbidities in Alzheimer's disease (AD). Seizures in AD have been shown to occur more often with early-onset disease, particularly when there is a familial presenilin I (PS1) mutation or abnormal expression of amyloid precursor protein (APP). AD patients with seizures have been associated with a faster decline in cognitive functions. However, it remains unclear how seizures exacerbate neurodegeneration in AD. Here, we showed that, using a kainic acid-induced acute seizure model, mitochondrial function is enhanced and the reactive oxygen species (ROS) are reduced in the brain of wild-type (WT) mice but not in an AD mouse model, APP/PS1 mice. These data suggest a lack of protective mechanism following seizures in APP/PS1 mice. Mechanistically, we found that an E3 ubiquitin ligase, the neural precursor cell-expressed developmentally downregulated protein 4-like (Nedd4-2), is elevated but stays dephosphorylated in APP/PS1 mice upon seizure inductions. Immunocytochemistry and sub-cellular fractionation experiments demonstrate an interaction between Nedd4-2 and mitochondria. Unbiased proteomics analysis suggests that Nedd4-2 regulates the expression of multiple mitochondrial proteins including one of the key mitochondrial outer membrane proteins, Mitofusin 2 (MFN2). Upon seizure induction, Nedd4-2 exhibits elevated interaction with mitochondria and downregulates MFN2 in APP/PS1 mice but not in WT mice. These data suggest that seizures aggravate mitochondrial dysfunction in AD, and Nedd4-2, which acts as a negative mitochondrial regulator, contributes to this effect. Altogether, our findings illustrate a potential mechanism by which seizures exacerbate neurodegeneration in AD and suggest Nedd4-2 as a novel therapeutic target for AD patients with comorbid seizures.

  PublisherDOI

• Reversing Pathophysiology in Fragile X Syndrome Mice by Promoting PGC-1α and Mitochondrial Functions

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-15

  articleOpen accessSenior author

  ABSTRACT Fragile X syndrome (FXS) is the leading cause of intellectual disabilities and autism, but a disease-modifying strategy remains unavailable. Recent studies have suggested reduced mitochondrial functions in FXS. However, the mechanisms underlying mitochondrial defects and their impact on FXS pathophysiology remain largely unclear. Here, we reveal a reduction in the mitochondrial master regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the mouse model of FXS, the Fmr1 knockout (KO) mice. We show that this impairment is caused by the inactivity of the transcription factor cAMP-response element-binding protein (CREB) in Fmr1 KO mice. Using the small molecule ZLN005, which induces AMP-activated protein kinase (AMPK)- and CREB-dependent elevation of PGC-1α in Fmr1 KO mice, we observed significantly increased mitochondrial functions and dynamics in cultured neurons in vitro and in the hippocampus in vivo. Furthermore, ZLN005 elicited a wide range of beneficial effects in Fmr1 KO mice, including enhanced inhibitory synaptic transmission, reduced circuit hyperexcitability, improved hippocampal synaptic plasticity, reduced cortical gamma-band oscillations, and improved interhemispheric coherence. Most importantly, we observed improved cognition and reduced autism-like behaviors in ZLN005-treated Fmr1 KO mice. Together, our findings identify AMPK-CREB signaling and PGC-1α as promising and selective therapeutic targets for FXS and reveal the broad impact of restoring PGC-1α on FXS pathophysiology. One Sentence Summary Promoting PGC-1α Reverses FXS Pathophysiology.

  PublisherOA PDFDOI

• Modulating inter-mitochondrial contacts to increase membrane potential for mitigating blue light damage

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-25

  preprintOpen access

  Abstract Mitochondrial membrane potential (MMP) is essential for mitochondrial functions, yet current methods for modulating MMP lack precise spatial and temporal control. Here, we present an optogenetic system that enables reversible formation of inter-mitochondrial contacts (mito-contacts) with high spatiotemporal precision. Blue light stimulation induces rapid formation of mito-contacts, which fully dissipate upon cessation of illumination. These light-induced mito-contacts can enhance MMP, leading to increased ATP production under stress conditions. Moreover, in human retinal cells and C. elegans , high MMP induced by mito-contacts alleviates the deleterious effects of prolonged blue light exposure, restoring energy metabolism and extending organismal lifespan. This optogenetic approach provides a powerful tool for modulating MMP and offers potential therapeutic applications for diseases linked to mitochondrial dysfunction.

  PublisherOA PDFDOI

• Phosphatidylinositol-3-phosphate mediates Arc capsid secretion through the multivesicular body pathway

  Proceedings of the National Academy of Sciences · 2024-08-23 · 10 citations

  articleOpen access

  Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) is an immediate early gene that plays a vital role in learning and memory. Arc protein has structural and functional properties similar to viral Group-specific antigen (Gag) protein and mediates the intercellular RNA transfer through virus-like capsids. However, the regulators and secretion pathway through which Arc capsids maneuver cargos are unclear. Here, we identified that phosphatidylinositol-3-phosphate (PI3P) mediates Arc capsid assembly and secretion through the endosomal-multivesicular body (MVB) pathway. Indeed, reconstituted Arc protein preferably binds to PI3P. In HEK293T cells, Arc forms puncta that colocalize with FYVE, an endosomal PI3P marker, as well as Rab5 and CD63, early endosomal and MVB markers, respectively. Superresolution imaging resolves Arc accumulates within the intraluminal vesicles of MVB. CRISPR double knockout of RalA and RalB, crucial GTPases for MVB biogenesis and exocytosis, severely reduces the Arc-mediated RNA transfer efficiency. RalA/B double knockdown in cultured rat cortical neurons increases the percentage of mature dendritic spines. Intake of extracellular vesicles purified from Arc-expressing wild-type, but not RalA/B double knockdown, cells in mouse cortical neurons reduces their surface GlutA1 levels. These results suggest that unlike the HIV Gag, whose membrane targeting requires interaction with plasma-membrane-specific phosphatidyl inositol (4,5) bisphosphate (PI(4,5)P2), the assembly of Arc capsids is mediated by PI3P at endocytic membranes. Understanding Arc's secretion pathway helps gain insights into its role in intercellular cargo transfer and highlights the commonality and distinction of trafficking mechanisms between structurally resembled capsid proteins.

  PublisherDOI

• mGluR7 allosteric modulator AMN082 corrects protein synthesis and pathological phenotypes in FXS

  EMBO Molecular Medicine · 2024-02-19 · 6 citations

  articleOpen accessSenior author

  Fragile X syndrome (FXS) is the leading cause of inherited autism and intellectual disabilities. Aberrant protein synthesis due to the loss of fragile X messenger ribonucleoprotein (FMRP) is the major defect in FXS, leading to a plethora of cellular and behavioral abnormalities. However, no treatments are available to date. In this study, we found that activation of metabotropic glutamate receptor 7 (mGluR7) using a positive allosteric modulator named AMN082 represses protein synthesis through ERK1/2 and eIF4E signaling in an FMRP-independent manner. We further demonstrated that treatment of AMN082 leads to a reduction in neuronal excitability, which in turn ameliorates audiogenic seizure susceptibility in Fmr1 KO mice, the FXS mouse model. When evaluating the animals' behavior, we showed that treatment of AMN082 reduces repetitive behavior and improves learning and memory in Fmr1 KO mice. This study uncovers novel functions of mGluR7 and AMN082 and suggests the activation of mGluR7 as a potential therapeutic approach for treating FXS.

  PublisherOA PDFDOI

• Hyperfunction of post-synaptic density protein 95 promotes seizure response in early-stage aβ pathology

  EMBO Reports · 2024-02-27 · 10 citations

  articleOpen accessSenior author

  Accumulation of amyloid-beta (Aβ) can lead to the formation of aggregates that contribute to neurodegeneration in Alzheimer's disease (AD). Despite globally reduced neural activity during AD onset, recent studies have suggested that Aβ induces hyperexcitability and seizure-like activity during the early stages of the disease that ultimately exacerbate cognitive decline. However, the underlying mechanism is unknown. Here, we reveal an Aβ-induced elevation of postsynaptic density protein 95 (PSD-95) in cultured neurons in vitro and in an in vivo AD model using APP/PS1 mice at 8 weeks of age. Elevation of PSD-95 occurs as a result of reduced ubiquitination caused by Akt-dependent phosphorylation of E3 ubiquitin ligase murine-double-minute 2 (Mdm2). The elevation of PSD-95 is consistent with the facilitation of excitatory synapses and the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induced by Aβ. Inhibition of PSD-95 corrects these Aβ-induced synaptic defects and reduces seizure activity in APP/PS1 mice. Our results demonstrate a mechanism underlying elevated seizure activity during early-stage Aβ pathology and suggest that PSD-95 could be an early biomarker and novel therapeutic target for AD.

  PublisherDOI

• Sustainable synthesis of carbon dots via bio‐waste recycling for biomedical imaging

  Smart Medicine · 2024-07-17 · 10 citations

  articleOpen access

  Abstract Bio‐waste is a side product of biomedical research containing carbon, which can be utilized for developing carbon dots (CDs). CDs are known to be useful for a variety of applications because of their unique photoluminescence, low toxicity, and straightforward synthesis. In this paper, we employed a one‐step hydrothermal method to prepare CDs from bio‐waste as the only reactant. The as‐synthesized Cell‐CDs were found to be chemically stable and biocompatible. In addition, the spectra of Cell‐CDs ’ emissions covered the visible light, which is ideal for super‐resolution imaging. Particularly, dual‐color imaging can be achieved, for example, by staining the plasma membrane with Cell‐CDs emitting one color and staining cytosolic organelles with Cell‐CDs emitting a different color of fluorescence. Here, we demonstrate such applications by studying the subcellular dynamics of live cells.

  PublisherOA PDFDOI

• <i>Tmod2</i>is a regulator of cocaine responses through control of striatal and cortical excitability, and drug-induced plasticity

  Journal of Neuroscience · 2024-03-20 · 3 citations

  articleOpen access

  Drugs of abuse induce neuroadaptations, including synaptic plasticity, that are critical for transition to addiction, and genes and pathways that regulate these neuroadaptations are potential therapeutic targets. Tropomodulin 2 ( Tmod2 ) is an actin-regulating gene that plays an important role in synapse maturation and dendritic arborization and has been implicated in substance-abuse and intellectual disability in humans. Here we mine the KOMP2 data and find that Tmod 2 knockout mice show emotionality phenotypes that are predictive of addiction vulnerability. Detailed addiction phenotyping showed that Tmod2 deletion does not affect the acute locomotor response to cocaine administration. However, sensitized locomotor responses are highly attenuated in these knockouts, indicating perturbed drug-induced plasticity. In addition, Tmod2 mutant animals do not self-administer cocaine indicating lack of hedonic responses to cocaine. Whole brain MR imaging shows differences in brain volume across multiple regions although transcriptomic experiments did not reveal perturbations in gene co-expression networks. Detailed electrophysiological characterization of Tmod2 KO neurons, showed increased spontaneous firing rate of early postnatal and adult cortical and striatal neurons. Cocaine-induced synaptic plasticity that is critical for sensitization is either missing or reciprocal in Tmod2 KO nucleus accumbens shell medium spiny neurons, providing a mechanistic explanation of the cocaine response phenotypes. Combined, these data collected from both males and females, provide compelling evidence that Tmod2 is a major regulator of plasticity in the mesolimbic system and regulates the reinforcing and addictive properties of cocaine. Significance statement We identify, characterize, and establish tropomodulin 2 (Tmod2), an actin-regulating gene exclusively expressed in neurons, as an important regulator of addiction-related phenotypes. We show that Tmod2 , knockout mice ( Tmod2 KO ) exhibit phenotypes that are predictive of addiction. In detailed addiction phenotyping, we find the Tmod2 regulates cocaine sensitization and self-administration. We explore anatomical, transcriptional, electrophysiological mechanisms of this regulation. Combined these studies provide compelling evidence that Tmod2 is critical for synaptic plasticity necessary for transition to addiction.

  PublisherOA PDFDOI

Recent grants

• Study of PAK3 in epilepsy-associated defects in synaptic plasticity

  NIH · $146k · 2020–2022

• NIH Grant F32HD069111

  NIH · $161k · 2014

• AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

  NIH · $2.1M · 2018–2025

Frequent coauthors

• Li‐Na Wei

  26 shared

• Hee Jung Chung

  University of Illinois Urbana-Champaign

  17 shared

• Kwan Young Lee

  University of Illinois Urbana-Champaign

  16 shared

• M. D. Mostaqul Huq

  University of Minnesota

  10 shared

• Dai-Chi Liu

  University of Illinois Urbana-Champaign

  10 shared

• Pawan Gupta

  Academy of Scientific and Innovative Research

  10 shared

• Jiuhe Zhu

  University of Illinois Urbana-Champaign

  10 shared

• R. Mark Henkelman

  Toronto Public Health

  9 shared

Labs

• Tsai Lab at UIUCPI

Awards & honors

• James and Maxine Heath Excellence in Teaching Award (2020)
• Arnold O. Beckman Research Award (2019)
• Teachers Ranked as Excellent (2016 - 2024)
• NARSAD Young Investigator Award (2015, 2018)
• Simons Foundation Autism Initiative-Explorer Award (2014)