Bingwei Lu, Postdoctoral Faculty Sponsor
Prevention of ribosome collision-induced neuromuscular degeneration by SARS CoV-2-encoded Nsp1.
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (42): e2202322119
An overarching goal of aging and age-related neurodegenerative disease research is to discover effective therapeutic strategies applicable to a broad spectrum of neurodegenerative diseases. Little is known about the extent to which targetable pathogenic mechanisms are shared among these seemingly diverse diseases. Translational control is critical for maintaining proteostasis during aging. Gaining control of the translation machinery is also crucial in the battle between viruses and their hosts. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic. Here, we show that overexpression of SARS-CoV-2-encoded nonstructural protein 1 (Nsp1) robustly rescued neuromuscular degeneration and behavioral phenotypes in Drosophila models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These diseases share a common mechanism: the accumulation of aberrant protein species due to the stalling and collision of translating ribosomes, leading to proteostasis failure. Our genetic and biochemical analyses revealed that Nsp1 acted in a multipronged manner to resolve collided ribosomes, abort stalled translation, and remove faulty translation products causative of disease in these models, at least in part through the ribosome recycling factor ABCE1, ribosome-associated quality-control factors, autophagy, and AKT signaling. Nsp1 exhibited exquisite specificity in its action, as it did not modify other neurodegenerative conditions not known to be associated with ribosome stalling. These findings uncover a previously unrecognized mechanism of Nsp1 in manipulating host translation, which can be leveraged for combating age-related neurodegenerative diseases that are affecting millions of people worldwide and currently without effective treatment.
View details for DOI 10.1073/pnas.2202322119
View details for PubMedID 36170200
Early Mitochondrial Fragmentation and Dysfunction in a Drosophila Model for Alzheimer's Disease
2021; 58 (1): 143-155
Many different cellular systems and molecular processes become compromised in Alzheimer's disease (AD) including proteostasis, autophagy, inflammatory responses, synapse and neuronal circuitry, and mitochondrial function. We focused in this study on mitochondrial dysfunction owing to the toxic neuronal environment produced by expression of Aβ42, and its relationship to other pathologies found in AD including increased neuronal apoptosis, plaque deposition, and memory impairment. Using super-resolution microscopy, we have assayed mitochondrial status in the three distinct neuronal compartments (somatic, dendritic, axonal) of mushroom body neurons of Drosophila expressing Aβ42. The mushroom body neurons comprise a major center for olfactory memory formation in insects. We employed calcium imaging to measure mitochondrial function, immunohistochemical and staining techniques to measure apoptosis and plaque formation, and olfactory classical conditioning to measure learning. We found that mitochondria become fragmented at a very early age along with decreased function measured by mitochondrial calcium entry. Increased apoptosis and plaque deposition also occur early, yet interestingly, a learning impairment was found only after a much longer period of time-10 days, which is a large fraction of the fly's lifespan. This is similar to the pronounced delay between cellular pathologies and the emergence of a memory dysfunction in humans. Our studies are consistent with the model that mitochondrial dysfunction and/or other cellular pathologies emerge at an early age and lead to much later learning impairments. The results obtained further develop this Drosophila model as a useful in vivo system for probing the mechanisms by which Aβ42 produces mitochondrial and other cellular toxicities that produce memory dysfunction.
View details for DOI 10.1007/s12035-020-02107-w
View details for Web of Science ID 000567739200002
View details for PubMedID 32909149
View details for PubMedCentralID PMC7704861
Pontin/Tip49 negatively regulates JNK-mediated cell death in Drosophila
CELL DEATH DISCOVERY
2018; 4: 8
Pontin (Pont), also known as Tip49, encodes a member of the AAA+ (ATPases Associated with Diverse Cellular Activities) superfamily and plays pivotal roles in cell proliferation and growth, yet its function in cell death has remained poorly understood. Here we performed a genetic screen for dominant modifiers of Eiger-induced JNK-dependent cell death in Drosophila, and identified Pont as a negative regulator of JNK-mediated cell death. In addition, loss of function of Pont is sufficient to induce cell death and activate the transcription of JNK target gene puc. Furthermore, the epistasis analysis indicates that Pont acts downstream of Hep. Finally, we found that Pont is also required for JNK-mediated thorax development and acts as a negative regulator of JNK phosphorylation. Together, our data suggest that pont encodes a negative component of Egr/JNK signaling pathway in Drosophila through negatively regulating JNK phosphorylation, which provides a novel role of ATPase in Egr-JNK signaling.
View details for DOI 10.1038/s41420-018-0074-1
View details for Web of Science ID 000463150000001
View details for PubMedID 30062057
View details for PubMedCentralID PMC6060144
FoxO mediates APP-induced AICD-dependent cell death
CELL DEATH & DISEASE
2014; 5: e1233
The amyloid precursor protein (APP) is a broadly expressed transmembrane protein that has a significant role in the pathogenesis of Alzheimer's disease (AD). APP can be cleaved at multiple sites to generate a series of fragments including the amyloid β (Aβ) peptides and APP intracellular domain (AICD). Although Aβ peptides have been proposed to be the main cause of AD pathogenesis, the role of AICD has been underappreciated. Here we report that APP induces AICD-dependent cell death in Drosophila neuronal and non-neuronal tissues. Our genetic screen identified the transcription factor forkhead box O (FoxO) as a crucial downstream mediator of APP-induced cell death and locomotion defect. In mammalian cells, AICD physically interacts with FoxO in the cytoplasm, translocates with FoxO into the nucleus upon oxidative stress, and promotes FoxO-induced transcription of pro-apoptotic gene Bim. These data demonstrate that APP modulates FoxO-mediated cell death through AICD, which acts as a transcriptional co-activator of FoxO.
View details for DOI 10.1038/cddis.2014.196
View details for Web of Science ID 000337229300033
View details for PubMedID 24832605
View details for PubMedCentralID PMC4047897
Snail modulates JNK-mediated cell death in Drosophila
CELL DEATH & DISEASE
2019; 10: 893
Cell death plays a pivotal role in animal development and tissue homeostasis. Dysregulation of this process is associated with a wide variety of human diseases, including developmental and immunological disorders, neurodegenerative diseases and tumors. While the fundamental role of JNK pathway in cell death has been extensively studied, its down-stream regulators and the underlying mechanisms remain largely elusive. From a Drosophila genetic screen, we identified Snail (Sna), a Zinc-finger transcription factor, as a novel modulator of ectopic Egr-induced JNK-mediated cell death. In addition, sna is essential for the physiological function of JNK signaling in development. Our genetic epistasis data suggest that Sna acts downstream of JNK to promote cell death. Mechanistically, JNK signaling triggers dFoxO-dependent transcriptional activation of sna. Thus, our findings not only reveal a novel function and the underlying mechanism of Sna in modulating JNK-mediated cell death, but also provide a potential drug target and therapeutic strategies for JNK signaling-related diseases.
View details for DOI 10.1038/s41419-019-2135-7
View details for Web of Science ID 000499743700006
View details for PubMedID 31772150
View details for PubMedCentralID PMC6879600
Pontin/Tip49 negatively regulates JNK-mediated cell death in Drosophila
CELL DEATH DISCOVERY
View details for Web of Science ID 000493284500010
APLP2 Modulates JNK-Dependent Cell Migration in Drosophila
BIOMED RESEARCH INTERNATIONAL
2018; 2018: 7469714
Amyloid precursor-like protein 2 (APLP2) belongs to the APP family and is widely expressed in human cells. Though previous studies have suggested a role of APLP2 in cancer progression, the exact role of APLP2 in cell migration remains elusive. Here in this report, we show that ectopic expression of APLP2 in Drosophila induces cell migration which is mediated by JNK signaling, as loss of JNK suppresses while gain of JNK enhances such phenotype. APLP2 is able to activate JNK signaling by phosphorylation of JNK, which triggers the expression of matrix metalloproteinase MMP1 required for basement membranes degradation to promote cell migration. The data presented here unraveled an in vivo role of APLP2 in JNK-mediated cell migration.
View details for DOI 10.1155/2018/7469714
View details for Web of Science ID 000440154500001
View details for PubMedID 30155482
View details for PubMedCentralID PMC6093063
Amyloid precursor like protein-1 promotes JNK-mediated cell migration in Drosophila
2017; 8 (30): 49725-49734
The amyloid precursor like protein-1 (APLP1) is a member of the amyloid precursor protein (APP) family in mammals. While many studies have been focused on the pathologic role of APP in Alzheimer's disease, the physiological functions of APLP1 have remained largely elusive. Here we report that ectopic expression of APLP1 in Drosophila induces cell migration, which is suppressed by the loss of JNK signaling and enhanced by the gain of JNK signaling. APLP1 activates JNK signaling through phosphorylation of JNK, which up-regulates the expression of matrix metalloproteinase MMP1 required for basement membranes degradation and promotes actin remodeling essential for cell migration. Our data thus provide the first in vivo evidence for a cell-autonomous role of APLP1 protein in migration.
View details for DOI 10.18632/oncotarget.17681
View details for Web of Science ID 000406232400101
View details for PubMedID 28537903
View details for PubMedCentralID PMC5564802
Or47b plays a role in Drosophila males' preference for younger mates
2016; 6 (6)
Reproductive behaviour is important for animals to keep their species existing on Earth. A key question is how to generate more and healthier progenies by choosing optimal mates. In Drosophila melanogaster, males use multiple sensory cues, including vision, olfaction and gustation, to achieve reproductive success. These sensory inputs are important, yet not all these different modalities are simultaneously required for courtship behaviour to occur. Moreover, the roles of these sensory inputs for male courtship choice remain largely unknown. Here, we demonstrate that males court younger females with greater preference and that olfactory inputs are indispensable for this male courtship choice. Specifically, the olfactory receptor Or47b is required for males to discriminate younger female mates from older ones. In combination with our previous work indicating that gustatory perception is necessary for this preference behaviour, our current study demonstrates the requirement of both olfaction and gustation in Drosophila males' courtship preference, thus providing new insights into the role of sensory cues in reproductive behaviour and success.
View details for DOI 10.1098/rsob.160086
View details for Web of Science ID 000377936600005
View details for PubMedID 27278650
View details for PubMedCentralID PMC4929943
APLP1 promotes dFoxO-dependent cell death in Drosophila
2015; 20 (6): 778-786
The amyloid precursor like protein-1 (APLP1) belongs to the amyloid precursor protein family that also includes the amyloid precursor protein (APP) and the amyloid precursor like protein-2 (APLP2). Though the three proteins share similar structures and undergo the same cleavage processing by α-, β- and γ-secretases, APLP1 shows divergent subcellular localization from that of APP and APLP2, and thus, may perform distinct roles in vivo. While extensive studies have been focused on APP, which is implicated in the pathogenesis of Alzheimer's disease, the functions of APLP1 remain largely elusive. Here we report that the expression of APLP1 in Drosophila induces cell death and produces developmental defects in wing and thorax. This function of APLP1 depends on the transcription factor dFoxO, as the depletion of dFoxO abrogates APLP1-induced cell death and adult defects. Consistently, APLP1 up-regulates the transcription of dFoxO target hid and reaper-two well known pro-apoptotic genes. Thus, the present study provides the first in vivo evidence that APLP1 is able to induce cell death, and that FoxO is a crucial downstream mediator of APLP1's activity.
View details for DOI 10.1007/s10495-015-1097-1
View details for Web of Science ID 000352789700002
View details for PubMedID 25740230
Gr33a Modulates Drosophila Male Courtship Preference
2015; 5: 7777
In any gamogenetic species, attraction between individuals of the opposite sex promotes reproductive success that guarantees their thriving. Consequently, mate determination between two sexes is effortless for an animal. However, choosing a spouse from numerous attractive partners of the opposite sex needs deliberation. In Drosophila melanogaster, both younger virgin females and older ones are equally liked options to males; nevertheless, when given options, males prefer younger females to older ones. Non-volatile cuticular hydrocarbons, considered as major pheromones in Drosophila, constitute females' sexual attraction that act through males' gustatory receptors (Grs) to elicit male courtship. To date, only a few putative Grs are known to play roles in male courtship. Here we report that loss of Gr33a function or abrogating the activity of Gr33a neurons does not disrupt male-female courtship, but eliminates males' preference for younger mates. Furthermore, ectopic expression of human amyloid precursor protein (APP) in Gr33a neurons abolishes males' preference behavior. Such function of APP is mediated by the transcription factor forkhead box O (dFoxO). These results not only provide mechanistic insights into Drosophila male courtship preference, but also establish a novel Drosophila model for Alzheimer's disease (AD).
View details for DOI 10.1038/srep07777
View details for Web of Science ID 000347839200007
View details for PubMedID 25586066
View details for PubMedCentralID PMC4648378
Aging-related neurodegeneration eliminates male courtship choice in Drosophila
NEUROBIOLOGY OF AGING
2014; 35 (9): 2174-2178
Choices between 2 options, one liked and one disliked, are effortless for an animal, whereas those among 2 equally liked options are more difficult to determine and might depend on an unknown mechanism. Here, we report that in the fruit fly Drosophila melanogaster, both younger virgin females and older ones are "liked options" to males. However, when given the choice, males tend to be fastidious and prefer younger virgin females to older ones. Besides, aging eliminates males' preference for younger mates, which can be mimicked by ectopically expressing the human amyloid precursor protein in their central nervous system. Furthermore, we examined the effect of neurodegeneration in Drosophila courtship circuit and confirmed that male courtship preference for younger mates was abrogated by neurodegeneration. Our work, thus characterizes a novel choice behavior that can be decisions after comparison and also reveals the critical role of neurodegeneration in this behavior, which provides new insights on decision-making mechanisms.
View details for DOI 10.1016/j.neurobiolaging.2014.02.026
View details for Web of Science ID 000338195100027
View details for PubMedID 24684795