About

Robert Reenan is a Professor of Biology who trained as a graduate student at Harvard Medical School in the laboratory of Dr. Richard Kolodner, where he studied DNA repair in yeast and discovered genes significant in human cancer. He pursued post-doctoral work at the University of Wisconsin-Madison in the Laboratory of Genetics under Dr. Barry Ganetzky, focusing on behavioral neurogenetics and ion channel genes in fruit flies. Reenan began his independent research career at the University of Connecticut Medical School in the Department of Genetics, where he discovered the process of RNA editing in the nervous system of Drosophila. He joined Brown University in 2006, where his research areas include aging, neurodegenerative diseases such as ALS and Alzheimer's, gene expression, genomics, ion channels, RNA splicing, and neural transmission. His work has contributed to understanding the molecular mechanisms underlying neural function and behavior, particularly through the study of RNA editing and ion channel regulation in model organisms. Reenan's research has advanced knowledge in neurogenetics, RNA biology, and the genetic basis of neurological diseases.

Research topics

• Medicine
• Pathology
• Genetics
• Biology
• Anatomy
• Neuroscience

Selected publications

• Age-dependent degeneration of an identified adult leg motor neuron in a <i>Drosophila</i> SOD1 model of ALS

  Biology Open · 2020 · 7 citations

  • Biology
  • Genetics
  • Anatomy

  model of ALS that recapitulate an important aspect of the human disease.This article has an associated First Person interview with the first author of the paper.

  PublisherDOI

• Circuit Dysfunction in <i>SOD1-ALS</i> Model First Detected in Sensory Feedback Prior to Motor Neuron Degeneration Is Alleviated by BMP Signaling

  Journal of Neuroscience · 2019-01-18 · 44 citations

  articleOpen access

  Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which the origin and underlying cellular defects are not fully understood. Although motor neuron degeneration is the signature feature of ALS, it is not clear whether motor neurons or other cells of the motor circuit are the site of disease initiation. To better understand the contribution of multiple cell types in ALS, we made use of a Drosophila Sod1 G85R knock-in model, in which all cells harbor the disease allele. End-stage dSod1 G85R animals of both sexes exhibit severe motor deficits with clear degeneration of motor neurons. Interestingly, earlier in dSod1 G85R larvae, motor function is also compromised, but their motor neurons exhibit only subtle morphological and electrophysiological changes that are unlikely to cause the observed decrease in locomotion. We analyzed the intact motor circuit and identified a defect in sensory feedback that likely accounts for the altered motor activity of dSod1 G85R . We found cell-autonomous activation of bone morphogenetic protein signaling in proprioceptor sensory neurons which are critical for the relay of the contractile status of muscles back to the central nerve cord, completely rescues early-stage motor defects and partially rescue late-stage motor function to extend lifespan. Identification of a defect in sensory feedback as a potential initiating event in ALS motor dysfunction, coupled with the ability of modified proprioceptors to alleviate such motor deficits, underscores the critical role that nonmotor neurons play in disease progression and highlights their potential as a site to identify early-stage ALS biomarkers and for therapeutic intervention. SIGNIFICANCE STATEMENT At diagnosis, many cellular processes are already disrupted in the amyotrophic lateral sclerosis (ALS) patient. Identifying the initiating cellular events is critical for achieving an earlier diagnosis to slow or prevent disease progression. Our findings indicate that neurons relaying sensory information underlie early stage motor deficits in a Drosophila knock-in model of ALS that best replicates gene dosage in familial ALS (fALS). Importantly, studies on intact motor circuits revealed defects in sensory feedback before evidence of motor neuron degeneration. These findings strengthen our understanding of how neural circuit dysfunctions lead to neurodegeneration and, coupled with our demonstration that the activation of bone morphogenetic protein signaling in proprioceptors alleviates both early and late motor dysfunction, underscores the importance of considering nonmotor neurons as therapeutic targets.

  PublisherOA PDFDOI

• Circuit dysfunction in SOD1-ALS model first detected in sensory feedback prior to motor neuron degeneration is alleviated by BMP signaling

  bioRxiv (Cold Spring Harbor Laboratory) · 2018-12-03 · 3 citations

  preprintOpen access

  Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose origin and underlying cellular defects are still not fully understood. While motor neuron degeneration is the signature feature of ALS, it is not yet clear if motor neurons, or other cells of the motor circuit, are the site of disease initiation. To better understand the contribution of multiple cell types in ALS, we made use of a Drosophila Sod1G85R knock-in model, in which all cells harbor the disease allele. End-stage dSod1G85R animals exhibit severe motor deficits with clear degeneration of motor neurons. Interestingly, earlier in dSod1G85R larvae motor function is also compromised, but their motor neurons exhibit only subtle morphological and electrophysiological changes, that are unlikely to cause the observed decrease in locomotion. We analyzed the intact motor circuit and identified a defect in sensory feedback that likely accounts for the altered motor activity of dSod1G85R. Furthermore, we found that the cell-autonomous activation of BMP signaling in proprioceptor sensory neurons that relay the contractile status of muscles back to the central nerve cord, is able to completely rescue early stage motor defects and partially rescue late stage motor function to extend lifespan. Identifying a defect in sensory feedback as a potential initiating event in ALS motor dysfunction, coupled with the ability of modified proprioceptors to alleviate such motor deficits, underscores the critical role that non-motor neurons play in disease progression and highlights their potential as a site to identify early-stage ALS biomarkers and for therapeutic intervention.

  PublisherOA PDFDOI

• Meta-analysis of Genetic Modifiers Reveals Candidate Dysregulated Pathways in Amyotrophic Lateral Sclerosis

  Neuroscience · 2018-12-26 · 21 citations

  reviewOpen access
  PublisherOA PDFDOI

• Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan

  Cell Reports · 2018-05-01 · 102 citations

  articleOpen access

  Transcriptional modulation of the process of autophagy involves the transcription factor HLH-30/TFEB. In order to systematically determine the regulatory network of HLH-30/TFEB, we performed a genome-wide RNAi screen in C. elegans and found that silencing the nuclear export protein XPO-1/XPO1 enhances autophagy by significantly enriching HLH-30 in the nucleus, which is accompanied by proteostatic benefits and improved longevity. Lifespan extension via xpo-1 silencing requires HLH-30 and autophagy, overlapping mechanistically with several established longevity models. Selective XPO1 inhibitors recapitulated the effect on autophagy and lifespan observed by silencing xpo-1 and protected ALS-afflicted flies from neurodegeneration. XPO1 inhibition in HeLa cells enhanced TFEB nuclear localization, autophagy, and lysosome biogenesis without affecting mTOR activity, revealing a conserved regulatory mechanism for HLH-30/TFEB. Altogether, our study demonstrates that altering the nuclear export of HLH-30/TFEB can regulate autophagy and establishes the rationale of targeting XPO1 to stimulate autophagy in order to prevent neurodegeneration.

  PublisherDOI

• Give me a SINE: how Selective Inhibitors of Nuclear Export modulate autophagy and aging

  Molecular & Cellular Oncology · 2018-08-17 · 10 citations

  articleOpen access

  Autophagy is a cellular recycling process leading to lysosomal degradation of damaged macromolecules, which can protect cells against aging. The transcription factor EB (TFEB), a major transcriptional regulator of genes involved in autophagy and lysosomal function, is emerging as an attractive target for pharmacological modulation. Recently, we demonstrated that inhibiting the function of nuclear export protein exportin 1 (XPO1 or CRM1) with RNAi or with selective inhibitors of nuclear export (SINE) results in the nuclear enrichment of TFEB and enhancement of autophagy in model organisms and human cells. In addition to current efforts to validate the use of SINE in cancer therapies, our work highlights the potential benefits of these drugs toward improving outcomes in neurodegenerative diseases and aging.

  PublisherOA PDFDOI

• Additional file 1 of Predicting RNA hyper-editing with a novel tool when unambiguous alignment is impossible

  Figshare · 2017-01-01

  articleOpen access

  Supplementary results. Descriptions of TE families with 1000 or more edit sites. (PDF 32 kb)

  PublisherDOI

• Additional file 4 of Predicting RNA hyper-editing with a novel tool when unambiguous alignment is impossible

  Figshare · 2017-01-01

  articleOpen access

  Supplementary methods. Detailed description of RepProfile prior and simplifications for EM. Also included: rationale for choosing to focus on FB4_DM, DNAREP1_DM and PROTOP. (PDF 133 kb)

  PublisherDOI

• Additional file 2 of Predicting RNA hyper-editing with a novel tool when unambiguous alignment is impossible

  Figshare · 2017-01-01

  datasetOpen access

  Supplementary tables. List of all editing predictions in FB4_DM, DNAREP1_DM and PROTOP along with sequences for the rdgA clones. (XLSX 1,065 kb)

  PublisherDOI

• Predicting RNA hyper-editing with a novel tool when unambiguous alignment is impossible

  BMC Genomics · 2017-07-10 · 1 citations

  articleOpen access

  BACKGROUND: Repetitive elements are now known to have relevant cellular functions, including self-complementary sequences that form double stranded (ds) RNA. There are numerous pathways that determine the fate of endogenous dsRNA, and misregulation of endogenous dsRNA is a driver of autoimmune disease, particularly in the brain. Unfortunately, the alignment of high-throughput, short-read sequences to repeat elements poses a dilemma: Such sequences may align equally well to multiple genomic locations. In order to differentiate repeat elements, current alignment methods depend on sequence variation in the reference genome. Reads are discarded when no such variations are present. However, RNA hyper-editing, a possible fate for dsRNA, introduces enough variation to distinguish between repeats that are otherwise identical. RESULTS: To take advantage of this variation, we developed a new algorithm, RepProfile, that simultaneously aligns reads and predicts novel variations. RepProfile accurately aligns hyper-edited reads that other methods discard. In particular we predict hyper-editing of Drosophila melanogaster repeat elements in vivo at levels previously described only in vitro, and provide validation by Sanger sequencing sixty-two individual cloned sequences. We find that hyper-editing is concentrated in genes involved in cell-cell communication at the synapse, including some that are associated with neurodegeneration. We also find that hyper-editing tends to occur in short runs. CONCLUSIONS: Previous studies of RNA hyper-editing discarded ambiguously aligned reads, ignoring hyper-editing in long, perfect dsRNA - the perfect substrate for hyper-editing. We provide a method that simulation and Sanger validation show accurately predicts such RNA editing, yielding a superior picture of hyper-editing.

  PublisherOA PDFDOI

Recent grants

• Genetic Suppression studies of human epilepsy mutations in a model genetic system

  NIH · $1.3M · 2011–2016

• Natural History and Functional Evolutionary Studies of A-to-I pre-mRNA Editing-ABR

  NSF · $150k · 2006–2007

• NIH Grant R01GM062291

  NIH · $1.0M · 2006

Frequent coauthors

• Yiannis A. Savva

  37 shared

• James E.C. Jepson

  National Hospital for Neurology and Neurosurgery

  30 shared

• Rachel Maloney

  Queen's University

  21 shared

• Georges St. Laurent

  St. Laurent Institute

  20 shared

• Kristi A. Wharton

  Brown University

  19 shared

• Aaron Held

  Harvard University

  19 shared

• Cynthia Staber

  Stowers Institute for Medical Research

  15 shared

• Diane Lipscombe

  Providence College

  15 shared

Education

• Ph.D., DNA repair in yeast

  Harvard Medical School

• Other, Behavioral neurogenetics, ion channel genes in the fruit fly

  University of Wisconsin-Madison

• M.D., RNA editing in the nervous system of the fly

  University of Connecticut Medical School