Neurotargets Fly Lab Understanding the pathogenic mechanisms underlying Neurodegenerative disorders
Neurodegenerative disorders, including Alzheimer’s disease (AD), frontotemporal dementia (FTLD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease and prion diseases, are some of the most dreaded conditions in our society. These conditions affect millions of people worldwide, represent a huge and increasing burden on the health-care system, and constitute one of the major challenges of modern medicine. Unfortunately, the pathogenic mechanisms underlying these debilitating disorders are poorly understood and, therefore, there are no effective therapies to avoid their fatal outcome.
The NeuroTargets Fly Lab focuses on the development and application of new technologies to define the molecular pathways leading to neurodegeneration and to identify potential therapeutic targets. To do so, we utilize the fruit fly Drosophila melanogaster to model molecular, biochemical and pathological aspects of human neurodegenerative conditions. This is achieved by disrupting homologous genes in Drosophila, or by expressing a human disease gene in this organism. Strikingly, the remarkable genetic conservation from flies to humans leads to neurological phenotypes that closely mimic the human disease. Once the model is validated, we apply a multidisciplinary approach combining Drosophila genetics, neurobiology, molecular biology, biochemistry, optogenetics and systems biology. Our goal is to to generate molecular portraits of these devastating disorders and dissect unknown, fundamental aspects of their pathologies.
Studying neurodegenerative diseases in fruit flies (Drosophila melanogaster) might seem unusual at first, but it has proven to be a valuable and relevant approach to understand the mechanisms underlying these disorders. Fruit flies share many genetic pathways and biological processes with humans. While the complexity of the nervous system differs between the two species, many of the fundamental cellular and molecular processes that underlie neurodegenerative diseases are highly conserved. This means that insights gained from studying fruit flies can provide valuable information about similar processes in humans. Interestingly, fruit flies exhibit various behaviors that can be easily quantified and monitored, such as locomotion, learning and memory. Impairments in these behaviors, therefore, serve as indicators of neurodegenerative disease progression. On the other hand, working with fruit fly models is generally more cost-efficient than using mammalian models. The rearing and maintenance of fruit flies are relatively inexpensive compared to larger animals. This cost-effectiveness allows researchers to conduct a larger number of experiments and trials, increasing the chances of finding effective therapeutic strategies. Moreover, while animal models are essential for understanding disease mechanisms and testing potential therapies, using lower-order organisms like fruit flies raises fewer ethical concerns than using mammals. This allows us to perform experiments that might not be feasible or ethically acceptable in larger animals. In conclusion, while flies don’t replicate the complexity of the human brain, they provide a powerful and cost-effective platform to explore genetic, molecular, and cellular processes that contribute to neurodegeneration.
Dr. Rincon-Limas received a bachelor degree on Biopharmaceutical Chemistry from the Autonomous University of Tamaulipas in Reynosa, Mexico. He also obtained a Master’s degree in Microbiology and a summa cum laude Ph.D. in Molecular Biology and Genetic Engineering at the Autonomous University of Nuevo Leon in Monterrey, Mexico. He then moved to Baylor College of Medicine in Houston to conduct his postdoctoral training in the Department of Human and Molecular Genetics, where he got training in Drosophila Genetics and Neurobiology. He got his first Faculty position in the Department of Neurology and the Mitchell Center for Neurodegenerative Disorders at the University of Texas Medical Branch in Galveston, and then moved to the University of Florida to join the Department of Neurology at the McKnight Brain Institute. He has a joint appointment in the Department of Neuroscience and is also a member of the UF Genetics Institute, the Center for Translational Research in Neurodegenerative Disease and the new Norman Fixel Institute for Neurological Diseases.
We recently obtained NIH funds to deconstruct the molecular pathology associated with TDP-43 toxicity in a fly model of ALS/FTLD expressing human mutant TDP-43. This model recapitulates key pathological features of the human disease including abnormal distribution, phosphorylation and aggregation of TDP-43 along with progressive neurodegeneration. Thus, we used these flies as discovery platform to uncover a diverse group of genes that robustly suppress toxicity of TDP-43 in vivo. Importantly, this effort led to the identification of genes and molecular pathways not previously known to be associated with ALS/FTLD. We are currently validating and
characterizing the role of these novel suppressors in the fly brain as well as in human cellular models of TDP-43 proteinopathies. We anticipate that these efforts will lead to the development of new and more efficient therapies for these incurable disorders.
A major goal of our lab is to discover new therapeutic targets to block Amyloid beta (Aβ) toxicity in fly models of Alzheimer’s disease (AD). AD is a complex neurodegenerative disorder with multiple underlying mechanisms and accumulation of Aβ in the human brain has been found to play a key role in disease pathogenesis. Studying Aβ deposition and toxicity using the power of Drosophila genetics can provide a better understanding of the molecular and cellular processes that lead to neuronal dysfunction and cognitive decline. Many cellular processes and molecular pathways are conserved across species and, thus, discovering therapeutic targets in fruit fly models can provide valuable information that may also be relevant in humans. The short lifespan and rapid reproduction cycle of Drosophila make it possible to test a large number of candidate genes (or potential drug candidates) for their ability to modify Aβ toxicity in a relatively short period of time. We are currently manipulating several new genes that can reduce or delay Aβ-induced neurodegeneration in the fly brain, which can lead to interventions to prevent or slow down the progression of neurodegeneration before irreversible damage occurs.
Amyloid plaques (composed of Aβ) and neurofibrillary tangles (composed of tau) are the two major pathological hallmarks of Alzheimer’s disease. Investigating how these two proteins interact and influence each other’s behavior is vital for understanding AD pathogenesis and for developing effective therapeutic strategies to stop or delay the loss of memory and cognitive decline. Recent studies suggests that Aβ and tau interact in a synergistic manner, potentially accelerating the progression of the disease. We recently performed a massive genetic screen in flies to uncover new targets that modulate concurrent Aβ and tau toxicity. Characterization of these new targets may shade light on the precise mechanisms by which these proteins influence each other’s aggregation and toxicity, and may lead to new therapeutic interventions targeting both proteins simultaneously.
Nuclear import receptors and nucleoporins play a crucial role in regulating the transport of molecules between the cytoplasm and the nucleus of cells. Proper nucleocytoplasmic transport is essential for maintaining cellular homeostasis and ensuring that the right molecules are present in the right cellular compartments. Dysfunction in this process can lead to the accumulation of toxic proteins in the wrong cellular compartments, contributing to the development of neurodegenerative diseases. Indeed, dysregulation of nucleocytoplasmic transport has been implicated in various neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer’s disease. We are currently investigating the role of the nuclear import receptor KPNB1 and other importins in fly models of neurodegenerative conditions, which may provide new potential targets for therapeutic interventions.
Meet the Team
Dr. Rincon-Limas is an expert in modeling human neurodegenerative disorders in fruit flies and has been working in this field for more than 20 years. He leads the NeuroTargets Fly Lab at the UF McKnight Brain Institute and his most relevant accomplishments are the generation of Drosophila models of Alzheimer’s disease, prion disorders, amyotrophic lateral sclerosis and frontotemporal dementia. His NIH-sponsored projects are aimed at producing discoveries with translational applications, like identifying new molecular targets through genetic screens in these models or through the judicious screening of molecules with therapeutic activity. With an overarching goal of unveiling the complexity of these disorders, Dr. Rincon-Limas aspires to paint comprehensive molecular portraits that offer insight into their underlying pathologies. Outside of work, he enjoys multiethnic cuisine, gardening, fishing, and spending quality time with family.
Deepak obtained his PhD degree in Molecular Neurobiology from the Indian Institute of Technology Jodhpur (IITJ) in Rajasthan, India, where he worked on the role of Protein Quality Control E3 ubiquitin ligases in neurodegeneration. He is currently investigating the role of proteolytic TDP-43 fragments in fly models of amyotrophic lateral sclerosis and is also studying new targets for therapeutic interventions based on discoveries from a massive loss-of-function screen.
Vanlal obtained her Ph.D. from the Indian Institute of Science (IISc) in Bangalore, India, working on the neuronal role of the Drosophila gene taxi in the regulation of flight behavior. She is currently investigating the neuroprotective role of several new genes that block concurrent Aβ and tau toxicity in the fly brain. In her spare time, she enjoys listening to songs and playing table tennis.
Swapnil received a Bachelor’s and Master’s degree in Biochemistry from Bundelkhand University, Jhansi, India. He also obtained a Ph.D. in Biological Sciences from the Academy of Scientific and Innovative Research, CSIR-NBRI, Lucknow, India. During his Ph.D. he studied the role of phytochemicals as anti-aging and neuroprotective agents using Caenorhabditis elegans. At present, he utilizes Drosophila genetics to understand the environmental and genetic factors associated with Alzheimer’s disease and TDP-43 proteinopathies. He loves to watch Bollywood movies, listen to songs, explore new places and go for the long drive.
Shivam graduated from Maharshi Dayanand University in India with a bachelor’s degree. Before joining the NeuroTargets Fly Lab, he conducted research on the role of neural circuits in memory formation using Drosophila as experimental system. He authored three papers and contributed to several book chapters in this area. He is currently assisting in the development of several behavioral platforms as well as in the characterization of new therapeutic targets for neurodegenerative diseases. In his free time, Shivam enjoys playing and watching basketball and badminton, which helps him find balance and inspiration.
Jeremy graduated recently at the University of Florida with a BSc degree in Chemistry. He is well versed in a variety of molecular biology and biochemical procedures as well as in Drosophila culture and manipulation. Jeremy is assisting technically in several projects associated with fly models of Alzheimer’s disease.
Rogina is a medical student at the University of Florida in the class of 2027. Before joining UF, she was an undergraduate research assistant at the Byrd Alzheimer’s Center at the University of South Florida, where she acquired skills in Drosophila manipulation and experimentation. Her current research focuses on the neuroprotective role of RNA polymerase subunits and other RNA associated factors in fly models of TDP-43 proteinopathies. Her work is supported by the UF Medical Honors Program and she plans to continue studying neurological disorders as clinician in the future.
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