Ching Chieh Chou

All Publications

• Small molecule C381 targets the lysosome to reduce inflammation and ameliorate disease in models of neurodegeneration Proc Natl Acad Sci U S A . Vest*, R. T., Chou*, C., Zhang, H., Haney, M. S., Li, L., Laqtom, N. N., Chang, B., Shuken, S., Nguyen, A., Yerra, L., Yang, A. C., Green, C., Tanga, M., Abu-Remaileh, M., Bassik, M. C., Frydman, J., Luo, J., Wyss-Coray, T. 2022; 119 (11): e2121609119

  View details for DOI 10.1073/pnas.2121609119

• TDP-43 Pathology Disrupts Nuclear Pore Complexes and Nucleocytoplasmic Transport in ALS/FTD NATURE NEUROSCIENCE Chou, C., Zhang, Y., Umoh, M. E., Vaughan, S. W., Lorenzini, I., Liu, F., Sayegh, M., Donlin-Asp, P. G., Chen, Y., Duong, D. M., Seyfried, N. T., Powers, M. A., Kukar, T., Hales, C. M., Gearing, M., Cairns, N. J., Boylan, K. B., Dickson, D. W., Rademakers, R., Zhang, Y., Petrucelli, L., Sattler, R., Zarnescu, D. C., Glass , J. D., Rossoll, W. 2018: 228–39

  Abstract

  The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.

  View details for DOI 10.1038/s41593-017-0047-3

  View details for PubMedCentralID PMC5800968

• PABPN1 suppresses TDP-43 toxicity in ALS disease models HUMAN MOLECULAR GENETICS Chou, C., Alexeeva, O. M., Yamada, S., Pribadi, A., Zhang, Y., Mo, B., Williams, K. R., Zarnescu, D. C., Rossoll, W. 2015; 24 (18): 5154-5173

  Abstract

  TAR DNA-binding protein 43 (TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. Here, we report poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. Overexpression of full-length PABPN1 but not a truncated version lacking the nuclear localization signal protects from pathogenic TDP-43-mediated toxicity, promotes the degradation of pathological TDP-43 and restores normal solubility and nuclear localization of endogenous TDP-43. Reduced levels of PABPN1 enhances the phenotypes in several cell culture and Drosophila models of ALS and results in the cytoplasmic mislocalization of TDP-43. Moreover, PABPN1 rescues the dysregulated stress granule (SG) dynamics and facilitates the removal of persistent SGs in TDP-43-mediated disease conditions. These findings demonstrate a role for PABPN1 in rescuing several cytopathological features of TDP-43 proteinopathy by increasing the turnover of pathologic proteins.

  View details for DOI 10.1093/hmg/ddv238

  View details for Web of Science ID 000361317200008

  View details for PubMedID 26130692

  View details for PubMedCentralID PMC4550816

• Increases of Quadriceps Inter-Muscular Cross-Correlation and Coherence during Exhausting Stepping Exercise SENSORS Chang, Y., Chou, C., Chan, H., Hsu, M., Yeh, M., Fang, C., Chuang, Y., Wei, S., Lien, H. 2012; 12 (12): 16353-16367

  Abstract

  The aim of this study was to examine the change of the intermuscular cross-correlation and coherence of the rectus femoris (RF), vastus medialis (VM) and vastus lateralis (VL) during exhausting stepping exercise. Eleven healthy adults repeated the stepping exercise up to their individual endurance limits (RPE score reached 20), and the cross-correlation and coherence were assessed by surface electromyography (EMG) recordings. The coefficient and time lag of cross-correlation and the coherence areas in the alpha (8-12 Hz), beta (15-30 Hz), gamma (30-60 Hz) and high-gamma (60-150 Hz) bands among the three muscle pairs (RF-VM, RF-VL and VM-VL) were calculated. As muscle fatigue, RF-VM and VM-VL showed increases of coefficients and the shortening of time lags. RF-VM and RF-VL showed increases of beta-band coherence in the ascent and descent phases, respectively. The increased intermuscular cross-correlation and beta-band coherence may be a compensatory strategy for maintaining the coordination of knee synergistic muscles during fatigue due to the fatigue-related disturbance of the corticospinal transmission. Therefore, the intermuscular cross-correlation and beta-band coherence may be a potential index for assessing muscle fatigue and monitoring the central control of motor function during dynamic fatiguing exercise.

  View details for DOI 10.3390/s121216353

  View details for Web of Science ID 000312607500020

  View details for PubMedID 23443382

  View details for PubMedCentralID PMC3571786

• Human tNeurons reveal aging-linked proteostasis deficits driving Alzheimer's phenotypes. Research square Chou, C. C., Vest, R., Prado, M. A., Wilson-Grady, J., Paulo, J. A., Shibuya, Y., Moran-Losada, P., Lee, T. T., Luo, J., Gygi, S. P., Kelly, J. W., Finley, D., Wernig, M., Wyss-Coray, T., Frydman, J. 2024

  Abstract

  Aging is a prominent risk factor for Alzheimer's disease (AD), but the cellular mechanisms underlying neuronal phenotypes remain elusive. Both accumulation of amyloid plaques and neurofibrillary tangles in the brain1 and age-linked organelle deficits2-7 are proposed as causes of AD phenotypes but the relationship between these events is unclear. Here, we address this question using a transdifferentiated neuron (tNeuron) model directly from human dermal fibroblasts. Patient-derived tNeurons retain aging hallmarks and exhibit AD-linked deficits. Quantitative tNeuron proteomic analyses identify aging and AD-linked deficits in proteostasis and organelle homeostasis, particularly affecting endosome-lysosomal components. The proteostasis and lysosomal homeostasis deficits in aged tNeurons are exacerbated in sporadic and familial AD tNeurons, promoting constitutive lysosomal damage and defects in ESCRT-mediated repair. We find deficits in neuronal lysosomal homeostasis lead to inflammatory cytokine secretion, cell death and spontaneous development of Aß and phospho-Tau deposits. These proteotoxic inclusions co-localize with lysosomes and damage markers and resemble inclusions in brain tissue from AD patients and APP-transgenic mice. Supporting the centrality of lysosomal deficits driving AD phenotypes, lysosome-function enhancing compounds reduce AD-associated cytokine secretion and Aβ deposits. We conclude that proteostasis and organelle deficits are upstream initiating factors leading to neuronal aging and AD phenotypes.

  View details for DOI 10.21203/rs.3.rs-4407236/v1

  View details for PubMedID 38853828

  View details for PubMedCentralID PMC11160905

• Human transdifferentiated neurons reveal lysosomal repair deficits in Alzheimer's disease Chou, C., Frydman, J. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2024

  View details for DOI 10.1016/j.ymgme.2023.107794

  View details for Web of Science ID 001192169300056

• Transdifferentiation: A Novel Tool for Disease Modeling and Translational Applications in Alzheimer's Disease Chou, C., Vest, R., Prado, M. A., Wilson-Grady, J., Paulo, J. A., Shibuya, Y., Moran-Losada, P., Lee, T., Luo, J., Gygi, S. P., Kelly, J. W., Finley, D. P., Wernig, M., Wyss-Coray, T., Frydman, J. WILEY. 2023: S205-S206

  View details for Web of Science ID 001084474200356

• A Comprehensive Enumeration of the Human Proteostasis Network. 2. Components of the Autophagy-Lysosome Pathway. bioRxiv : the preprint server for biology Elsasser, S., Elia, L. P., Morimoto, R. I., Powers, E. T., Finley, D., Costa, B., Budron, M., Tokuno, Z., Wang, S., Iyer, R. G., Barth, B., Mockler, E., Finkbeiner, S., Gestwicki, J. E., Richardson, R. A., Stoeger, T., Tan, E. P., Xiao, Q., Cole, C. M., Massey, L. A., Garza, D., Kelly, J. W., Rainbolt, T. K., Chou, C. C., Masto, V. B., Frydman, J., Nixon, R. A. 2023

  Abstract

  The condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Establishing and maintaining proteostasis is the province of the proteostasis network, approximately 2,700 components that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental entity in biology that is essential for cellular health and has direct relevance to many diseases of protein conformation. However, it is not well defined or annotated, which hinders its functional characterization in health and disease. In this series of manuscripts, we aim to operationally define the human proteostasis network by providing a comprehensive, annotated list of its components. We provided in a previous manuscript a list of chaperones and folding enzymes as well as the components that make up the machineries for protein synthesis, protein trafficking into and out of organelles, and organelle-specific degradation pathways. Here, we provide a curated list of 838 unique high-confidence components of the autophagy-lysosome pathway, one of the two major protein degradation systems in human cells.

  View details for DOI 10.1101/2023.03.22.533675

  View details for PubMedID 36993380

  View details for PubMedCentralID PMC10055369

• Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy. Molecular neurodegeneration Khalil, B., Chhangani, D., Wren, M. C., Smith, C. L., Lee, J. H., Li, X., Puttinger, C., Tsai, C. W., Fortin, G., Morderer, D., Gao, J., Liu, F., Lim, C. K., Chen, J., Chou, C. C., Croft, C. L., Gleixner, A. M., Donnelly, C. J., Golde, T. E., Petrucelli, L., Oskarsson, B., Dickson, D. W., Zhang, K., Shorter, J., Yoshimura, S. H., Barmada, S. J., Rincon-Limas, D. E., Rossoll, W. 2022; 17 (1): 80

  Abstract

  Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-β1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology.We used immunostaining, immunoprecipitation, biochemical and toxicity assays in cell lines, primary neuron and organotypic mouse brain slice cultures, to determine the impact of KPNB1 on the solubility, localization, and toxicity of pathological TDP-43 constructs. Postmortem patient brain and spinal cord tissue was stained to assess KPNB1 colocalization with TDP-43 inclusions. Turbidity assays were employed to study the dissolution and prevention of aggregation of recombinant TDP-43 fibrils in vitro. Fly models of TDP-43 proteinopathy were used to determine the effect of KPNB1 on their neurodegenerative phenotype in vivo.We discovered that several members of the nuclear import receptor protein family can reduce the formation of pathological TDP-43 aggregates. Using KPNB1 as a model, we found that its activity depends on the prion-like C-terminal region of TDP-43, which mediates the co-aggregation with phenylalanine and glycine-rich nucleoporins (FG-Nups) such as Nup62. KPNB1 is recruited into these co-aggregates where it acts as a molecular chaperone that reverses aberrant phase transition of Nup62 and TDP-43. These findings are supported by the discovery that Nup62 and KPNB1 are also sequestered into pathological TDP-43 aggregates in ALS/FTD postmortem CNS tissue, and by the identification of the fly ortholog of KPNB1 as a strong protective modifier in Drosophila models of TDP-43 proteinopathy. Our results show that KPNB1 can rescue all hallmarks of TDP-43 pathology, by restoring its solubility and nuclear localization, and reducing neurodegeneration in cellular and animal models of ALS/FTD.Our findings suggest a novel NLS-independent mechanism where, analogous to its canonical role in dissolving the diffusion barrier formed by FG-Nups in the nuclear pore, KPNB1 is recruited into TDP-43/FG-Nup co-aggregates present in TDP-43 proteinopathies and therapeutically reverses their deleterious phase transition and mislocalization, mitigating neurodegeneration.

  View details for DOI 10.1186/s13024-022-00585-1

  View details for PubMedID 36482422

• The Survival of Motor Neuron Protein Acts as a Molecular Chaperone for mRNP Assembly CELL REPORTS Donlin-Asp, P. G., Fallini, C., Campos, J., Chou, C., Merritt, M. E., Phan, H. C., Bassell, G. J., Rossoll, W. 2017; 18 (7): 1660-1673

  Abstract

  Spinal muscular atrophy (SMA) is a motor neuron disease caused by reduced levels of the survival of motor neuron (SMN) protein. SMN is part of a multiprotein complex that facilitates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). SMN has also been found to associate with mRNA-binding proteins, but the nature of this association was unknown. Here, we have employed a combination of biochemical and advanced imaging methods to demonstrate that SMN promotes the molecular interaction between IMP1 protein and the 3' UTR zipcode region of β-actin mRNA, leading to assembly of messenger ribonucleoprotein (mRNP) complexes that associate with the cytoskeleton to facilitate trafficking. We have identified defects in mRNP assembly in cells and tissues from SMA disease models and patients that depend on the SMN Tudor domain and explain the observed deficiency in mRNA localization and local translation, providing insight into SMA pathogenesis as a ribonucleoprotein (RNP)-assembly disorder.

  View details for DOI 10.1016/j.celrep.2017.01.059

  View details for Web of Science ID 000397324900009

  View details for PubMedID 28199839

  View details for PubMedCentralID PMC5492976

• Post-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALS CELL REPORTS Coyne, A. N., Lorenzini, I., Chou, C., Torvund, M., Rogers, R. S., Starr, A., Zaepfel, B. L., Levy, J., Johannesmeyer, J., Schwartz, J. C., Nishimune, H., Zinsmaier, K., Rossoll, W., Sattler, R., Zarnescu, D. C. 2017; 21 (1): 110-125

  View details for DOI 10.1016/j.celrep.2017.09.028

• Effects of Botulinum Toxin Landmark-Guided Intra-articular Injection in Subjects With Knee Osteoarthritis PM&R Hsieh, L., Wu, C., Chou, C., Yang, S., Wu, S., Lin, Y., Hsu, W. 2016; 8 (12): 1127-1135

  Abstract

  Increasing evidence has suggested that botulinum toxin A (BoNT/A) can inhibit the release of selected neuropeptide transmitters from primary sensory neurons. Thus, intra-articular (IA) injection therapies with BoNT/A may reduce pain in patients with knee osteoarthritis (OA).To investigate the effects of landmark-guided IA injection of BoNT/A on patients with knee OA.A prospective randomized controlled trial.A rehabilitation clinic of a private teaching hospital.A total of 46 patients with symptomatic knee OA (mostly Kellgren-Lawrence grade 2-3).The patients were randomly assigned to 1 of the following groups: BoNT/A group (BoNT/A injection; n = 21) or control group (education only; n = 20). The patients in the BoNT/A group received an IA injection of 100 units of BoNT/A into the affected knee.The short-term (1 week posttreatment) and long-term (6 months posttreatment) effects were evaluated using a pain visual analogue scale (VAS) and questionnaires concerning functional status, including the Lequesne and Western Ontario and McMaster Universities (WOMAC) indexes.The between-group comparison revealed significant differences with regard to the pain VAS score at 1 week (P < .001) and at 6 months (P = .001) posttreatment. Similar findings for the between-group comparison were observed for the WOMAC and Lequesne indexes at 6 months (P < .05) posttreatment. The pain VAS score in the BoNT/A group significantly decreased from 5.05 ± 1.12 (pretreatment) to 2.89 ± 1.04 at 1 week (P < .001) and 3.45 ± 1.70 at 6 months posttreatment (P < .001) but not in the control group (P = .476).The IA injection of BoNT/A provided pain relief and improved functional abilities in patients with knee OA in both the short- and long-term follow-up.I.

  View details for DOI 10.1016/j.pmrj.2016.05.009

  View details for Web of Science ID 000391085900001

  View details for PubMedID 27210235

• Robot-Assisted Passive Exercise for Ankle Hypertonia in Individuals with Chronic Spinal Cord Injury JOURNAL OF MEDICAL AND BIOLOGICAL ENGINEERING Fang, C., Hsu, M., Chen, C., Cheng, H. K., Chou, C., Chang, Y. 2015; 35 (4): 464-472

  View details for DOI 10.1007/s40846-015-0059-y

  View details for Web of Science ID 000360395300006

• Cycling Regimen Induces Spinal Circuitry Plasticity and Improves Leg Muscle Coordination in Individuals With Spinocerebellar Ataxia ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION Chang, Y., Chou, C., Huang, W., Lu, C., Wong, A. M., Hsu, M. 2015; 96 (6): 1006-1013

  Abstract

  To compare the reciprocal control of agonist and antagonist muscles in individuals with and without spinocerebellar ataxia (SCA) and to evaluate the effect of a 4-week leg cycling regimen on functional coordination and reciprocal control of agonist and antagonist muscles in patients with SCA.Randomized controlled trial with repeated measures.Research laboratory in a general hospital.Individuals with SCA (n=20) and without SCA (n=20).A single 15-minute session of leg cycling and a 4-week cycling regimen.Individuals with SCA (n=20) and without SCA (n=20) underwent disynaptic reciprocal inhibition and D1 inhibition tests of the soleus muscles before and after a single 15-minute cycling session. Individuals with SCA were randomly assigned to either participate in 4 weeks of cycling training (n=10) or to receive no training (n=10). The disynaptic reciprocal inhibition and D1 inhibition and International Cooperative Ataxia Rating Scale (ICARS) scores were evaluated in both groups after 4 weeks.Individuals with SCA showed abnormally strong resting values of disynaptic reciprocal inhibition and D1 inhibition (P<.001) and impaired inhibition modulation capacity after a single 15-minute session of cycling (P<.001). The inhibition modulation capacity was restored (P<.001), and the ICARS scores improved significantly (pre: 13.5±9.81, post: 11.3±8.74; P=.046) after 4 weeks of cycling training.A 4-week cycling regimen can normalize the modulation of reciprocal inhibition and functional performance in individuals with SCA. These findings are applicable to the coordination training of patients.

  View details for DOI 10.1016/j.apmr.2015.01.021

  View details for Web of Science ID 000356398200006

  View details for PubMedID 25668777

• Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord FRONTIERS IN NEURAL CIRCUITS Gozal, E. A., O'Neill, B. E., Sawchuk, M. A., Zhu, H., Halder, M., Chou, C., Hochman, S. 2014; 8

  Abstract

  The trace amines (TAs), tryptamine, tyramine, and β-phenylethylamine, are synthesized from precursor amino acids via aromatic-L-amino acid decarboxylase (AADC). We explored their role in the neuromodulation of neonatal rat spinal cord motor circuits. We first showed that the spinal cord contains the substrates for TA biosynthesis (AADC) and for receptor-mediated actions via trace amine-associated receptors (TAARs) 1 and 4. We next examined the actions of the TAs on motor activity using the in vitro isolated neonatal rat spinal cord. Tyramine and tryptamine most consistently increased motor activity with prominent direct actions on motoneurons. In the presence of N-methyl-D-aspartate, all applied TAs supported expression of a locomotor-like activity (LLA) that was indistinguishable from that ordinarily observed with serotonin, suggesting that the TAs act on common central pattern generating neurons. The TAs also generated distinctive complex rhythms characterized by episodic bouts of LLA. TA actions on locomotor circuits did not require interaction with descending monoaminergic projections since evoked LLA was maintained following block of all Na(+)-dependent monoamine transporters or the vesicular monoamine transporter. Instead, TA (tryptamine and tyramine) actions depended on intracellular uptake via pentamidine-sensitive Na(+)-independent membrane transporters. Requirement for intracellular transport is consistent with the TAs having much slower LLA onset than serotonin and for activation of intracellular TAARs. To test for endogenous actions following biosynthesis, we increased intracellular amino acid levels with cycloheximide. LLA emerged and included distinctive TA-like episodic bouts. In summary, we provided anatomical and functional evidence of the TAs as an intrinsic spinal monoaminergic modulatory system capable of promoting recruitment of locomotor circuits independent of the descending monoamines. These actions support their known sympathomimetic function.

  View details for DOI 10.3389/fncir.2014.00134

  View details for Web of Science ID 000346555800001

  View details for PubMedID 25426030

  View details for PubMedCentralID PMC4224135