Honors & Awards
Life Sciences Research Foundation Postdoctoral Fellowship, Open Philanthropy Project/Life Sciences Research Foundation (2019-2022)
Glenn Foundation for Medical Research Postdoctoral Fellowship in Aging Research, Glenn Foundation/American Federation for Aging Research (2018-2019)
Finalist, HHMI International Student Research Fellowship, Howard Hughes Medical Institute (2014)
Doctor of Philosophy, Emory University (2017)
Master of Science, National Yang-Ming University (2009)
Bachelor of Science, Chang Gung University (2007)
Judith Frydman, Postdoctoral Faculty Sponsor
Current Research and Scholarly Interests
I am interested in the cellular strategies to regulate protein folding, transport and aggregation, and the pathogenic pathways leading to proteome remodeling in age-related neurodegenerative diseases. I use molecular imaging, cell reprogramming and multi-omics technologies to address these questions with importance to the aging and neuroscience field.
TDP-43 Pathology Disrupts Nuclear Pore Complexes and Nucleocytoplasmic Transport in ALS/FTD
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
2015; 24 (18): 5154-5173
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
The Survival of Motor Neuron Protein Acts as a Molecular Chaperone for mRNP Assembly
2017; 18 (7): 1660-1673
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
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
2016; 8 (12): 1127-1135
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 2015; 35 (4): 464-472
Cycling Regimen Induces Spinal Circuitry Plasticity and Improves Leg Muscle Coordination in Individuals With Spinocerebellar Ataxia
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
2015; 96 (6): 1006-1013
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
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
Increases of Quadriceps Inter-Muscular Cross-Correlation and Coherence during Exhausting Stepping Exercise
2012; 12 (12): 16353-16367
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