Morgan Jennifer R.

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Morgan

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Jennifer R.

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0000-0001-9915-6360

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Swimming kinematics and performance of spinal transected lampreys with different levels of axon regeneration

(The Company of Biologists, 2021-11-05) Fies, Jacob ; Gemmell, Brad J. ; Fogerson, Stephanie M. ; Morgan, Jennifer R. ; Tytell, Eric D. ; Colin, Sean P.

Axon regeneration is critical for restoring neural function after spinal cord injury. This has prompted a series of studies on the neural and functional recovery of lampreys after spinal cord transection. Despite this, there are still many basic questions remaining about how much functional recovery depends on axon regeneration. Our goal was to examine how swimming performance is related to degree of axon regeneration in lampreys recovering from spinal cord transection by quantifying the relationship between swimming performance and percent axon regeneration of transected lampreys after 11 weeks of recovery. We found that while swimming speeds varied, they did not relate to percent axon regeneration. In fact, swimming speeds were highly variable within individuals, meaning that most individuals could swim at both moderate and slow speeds, regardless of percent axon regeneration. However, none of the transected individuals were able to swim as fast as the control lampreys. To swim fast, control lampreys generated high amplitude body waves with long wavelengths. Transected lampreys generated body waves with lower amplitude and shorter wavelengths than controls, and to compensate, transected lampreys increased their wave frequencies to swim faster. As a result, transected lampreys had significantly higher frequencies than control lampreys at comparable swimming velocities. These data suggest that the control lampreys swam more efficiently than transected lampreys. In conclusion, there appears to be a minimal recovery threshold in terms of percent axon regeneration required for lampreys to be capable of swimming; however, there also seems to be a limit to how much they can behaviorally recover.
α-Synuclein dimers impair vesicle fission during clathrin-mediated synaptic vesicle recycling

(Frontiers Media, 2017-12-11) Medeiros, Audrey T. ; Soll, Lindsey G. ; Tessari, Isabella ; Bubacco, Luigi ; Morgan, Jennifer R.

α-Synuclein is a presynaptic protein that regulates synaptic vesicle (SV) trafficking. In Parkinson’s disease (PD) and several other neurodegenerative disorders, aberrant oligomerization and aggregation of α-synuclein lead to synaptic dysfunction and neurotoxicity. Despite evidence that α-synuclein oligomers are generated within neurons under physiological conditions, and that altering the balance of monomers and oligomers contributes to disease pathogenesis, how each molecular species of α-synuclein impacts SV trafficking is currently unknown. To address this, we have taken advantage of lamprey giant reticulospinal (RS) synapses, which are accessible to acute perturbations via axonal microinjection of recombinant proteins. We previously reported that acute introduction of monomeric α-synuclein inhibited SV recycling, including effects on the clathrin pathway. Here, we report the effects of α-synuclein dimers at synapses. Similar to monomeric α-synuclein, both recombinant α-synuclein dimers that were evaluated bound to small liposomes containing anionic lipids in vitro, but with reduced efficacy. When introduced to synapses, the α-synuclein dimers also induced SV recycling defects, which included a build up of clathrin-coated pits (CCPs) with constricted necks that were still attached to the plasma membrane, a phenotype indicative of a vesicle fission defect. Interestingly, both α-synuclein dimers induced longer necks on CCPs as well as complex, branching membrane tubules, which were distinct from the CCPs induced by a dynamin inhibitor, Dynasore. In contrast, monomeric α-synuclein induced a buildup of free clathrin-coated vesicles (CCVs), indicating an inhibition of clathrin-mediated endocytosis at a later stage during the clathrin uncoating process. Taken together, these data further support the conclusion that excess α-synuclein impairs SV recycling. The data additionally reveal that monomeric and dimeric α-synuclein produce distinct effects on clathrin-mediated endocytosis, predicting different molecular mechanisms. Understanding what these mechanisms are could help to further elucidate the normal functions of this protein, as well as the mechanisms underlying PD pathologies.
Thrust generation during steady swimming and acceleration from rest in anguilliform swimmers

(Company of Biologists, 2019-11-18) Du Clos, Kevin T. ; Dabiri, John O. ; Costello, John H. ; Colin, Sean P. ; Morgan, Jennifer R. ; Fogerson, Stephanie M. ; Gemmell, Brad J.

Escape swimming is a crucial behavior by which undulatory swimmers evade potential threats. The hydrodynamics of escape swimming have not been well studied, particularly for anguilliform swimmers, such as the sea lamprey Petromyzon marinus. For this study, we compared the kinematics and hydrodynamics of larval sea lampreys with those of lampreys accelerating from rest during escape swimming. We used experimentally derived velocity fields to calculate pressure fields and distributions of thrust and drag along the body. Lampreys initiated acceleration from rest with the formation of a high-amplitude body bend at approximately one-quarter body length posterior to the head. This deep body bend produced two high-pressure regions from which the majority of thrust for acceleration was derived. In contrast, steady swimming was characterized by shallower body bends and negative-pressure-derived thrust, which was strongest near the tail. The distinct mechanisms used for steady swimming and acceleration from rest may reflect the differing demands of the two behaviors. High-pressure-based mechanisms, such as the one used for acceleration from rest, could also be important for low-speed maneuvering during which drag-based turning mechanisms are less effective. The design of swimming robots may benefit from the incorporation of such insights from unsteady swimming.
Axonal ensheathment in the nervous system of lamprey : implications for the evolution of myelinating glia

(Society for Neuroscience, 2018-07-18) Weil, Marie-Theres ; Heibeck, Saskia ; Töpperwien, Mareike ; tom Dieck, Susanne ; Ruhwedel, Torben ; Salditt, Tim ; Rodicio, María Celina ; Morgan, Jennifer R. ; Nave, Klaus-Armin ; Möbius, Wiebke ; Werner, Hauke B.

In the nervous system, myelination of axons enables rapid impulse conduction and is a specialized function of glial cells. Myelinating glia are the last cell type to emerge in the evolution of vertebrate nervous systems, presumably in ancient jawed vertebrates (gnathostomata) because jawless vertebrates (agnathans) lack myelin. We have hypothesized that, in these unmyelinated species, evolutionary progenitors of myelinating cells must have existed that should still be present in contemporary agnathan species. Here, we used advanced electron microscopic techniques to reveal axon–glia interactions in the sea lamprey Petromyzon marinus. By quantitative assessment of the spinal cord and the peripheral lateral line nerve, we observed a marked maturation-dependent growth of axonal calibers. In peripheral nerves, all axons are ensheathed by glial cells either in bundles or, when larger than the threshold caliber of 3 μm, individually. The ensheathing glia are covered by a basal lamina and express SoxE-transcription factors, features of mammalian Remak-type Schwann cells. In larval lamprey, the ensheathment of peripheral axons leaves gaps that are closed in adults. CNS axons are also covered to a considerable extent by glial processes, which contain a high density of intermediate filaments, glycogen particles, large lipid droplets, and desmosomes, similar to mammalian astrocytes. Indeed, by in situ hybridization, these glial cells express the astrocyte marker Aldh1l1. Specimens were of unknown sex. Our observations imply that radial sorting, ensheathment, and presumably also metabolic support of axons are ancient functions of glial cells that predate the evolutionary emergence of myelin in jawed vertebrates.
Regeneration in the era of functional genomics and gene network analysis

(Marine Biological Laboratory, 2011-08) Smith, Joel ; Morgan, Jennifer R. ; Zottoli, Steven J. ; Smith, Peter J. S. ; Buxbaum, Joseph D. ; Bloom, Ona E.

What gives an organism the ability to regrow tissues and to recover function where another organism fails is the central problem of regenerative biology. The challenge is to describe the mechanisms of regeneration at the molecular level, delivering detailed insights into the many components that are cross-regulated. In other words, a broad, yet deep dissection of the system-wide network of molecular interactions is needed. Functional genomics has been used to elucidate gene regulatory networks (GRNs) in developing tissues, which, like regeneration, are complex systems. Therefore, we reason that the GRN approach, aided by next generation technologies, can also be applied to study the molecular mechanisms underlying the complex functions of regeneration. We ask what characteristics a model system must have to support a GRN analysis. Our discussion focuses on regeneration in the central nervous system, where loss of function has particularly devastating consequences for an organism. We examine a cohort of cells conserved across all vertebrates, the reticulospinal (RS) neurons, which lend themselves well to experimental manipulations. In the lamprey, a jawless vertebrate, there are giant RS neurons whose large size and ability to regenerate make them particularly suited for a GRN analysis. Adding to their value, a distinct subset of lamprey RS neurons reproducibly fail to regenerate, presenting an opportunity for side-by-side comparison of gene networks that promote or inhibit regeneration. Thus, determining the GRN for regeneration in RS neurons will provide a mechanistic understanding of the fundamental cues that lead to success or failure to regenerate.
How the bending kinematics of swimming lampreys build negative pressure fields for suction thrust

(Company of Biologists, 2016-12-14) Gemmell, Brad J. ; Fogerson, Stephanie M. ; Costello, John H. ; Morgan, Jennifer R. ; Dabiri, John O. ; Colin, Sean P.

Swimming animals commonly bend their bodies to generate thrust. For undulating animals such as eels and lampreys, their bodies bend in the form of waves that travel from head to tail. These kinematics accelerate the flow of adjacent fluids, which alters the pressure field in a manner that generates thrust. We used a comparative approach to evaluate the cause-and-effect relationships in this process by quantifying the hydrodynamic effects of body kinematics at the body–fluid interface of the lamprey, Petromyzon marinus, during steady-state swimming. We compared the kinematics and hydrodynamics of healthy control lampreys to lampreys whose spinal cord had been transected mid-body, resulting in passive kinematics along the posterior half of their body. Using high-speed particle image velocimetry (PIV) and a method for quantifying pressure fields, we detail how the active bending kinematics of the control lampreys were crucial for setting up strong negative pressure fields (relative to ambient fields) that generated high-thrust regions at the bends as they traveled all along the body. The passive kinematics of the transected lamprey were only able to generate significant thrust at the tail, relying on positive pressure fields. These different pressure and thrust scenarios are due to differences in how active versus passive body waves generated and controlled vorticity. This demonstrates why it is more effective for undulating lampreys to pull, rather than push, themselves through the fluid.
α-Synuclein-112 impairs synaptic vesicle recycling consistent with its enhanced membrane binding properties

(Frontiers Media, 2020-05-29) Soll, Lindsey G. ; Eisen, Julia N. ; Vargas, Karina J. ; Medeiros, Audrey T. ; Hammar, Katherine M. ; Morgan, Jennifer R.

Synucleinopathies are neurological disorders associated with α-synuclein overexpression and aggregation. While it is well-established that overexpression of wild type α-synuclein (α-syn-140) leads to cellular toxicity and neurodegeneration, much less is known about other naturally occurring α-synuclein splice isoforms. In this study we provide the first detailed examination of the synaptic effects caused by one of these splice isoforms, α-synuclein-112 (α-syn-112). α-Syn-112 is produced by an in-frame excision of exon 5, resulting in deletion of amino acids 103–130 in the C-terminal region. α-Syn-112 is upregulated in the substantia nigra, frontal cortex, and cerebellum of parkinsonian brains and higher expression levels are correlated with susceptibility to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA). We report here that α-syn-112 binds strongly to anionic phospholipids when presented in highly curved liposomes, similar to α-syn-140. However, α-syn-112 bound significantly stronger to all phospholipids tested, including the phosphoinositides. α-Syn-112 also dimerized and trimerized on isolated synaptic membranes, while α-syn-140 remained largely monomeric. When introduced acutely to lamprey synapses, α-syn-112 robustly inhibited synaptic vesicle recycling. Interestingly, α-syn-112 produced effects on the plasma membrane and clathrin-mediated synaptic vesicle endocytosis that were phenotypically intermediate between those caused by monomeric and dimeric α-syn-140. These findings indicate that α-syn-112 exhibits enhanced phospholipid binding and oligomerization in vitro and consequently interferes with synaptic vesicle recycling in vivo in ways that are consistent with its biochemical properties. This study provides additional evidence suggesting that impaired vesicle endocytosis is a cellular target of excess α-synuclein and advances our understanding of potential mechanisms underlying disease pathogenesis in the synucleinopathies.
The synaptic vesicle cycle revisited: New insights into the modes and mechanisms

(Society for Neuroscience, 2019-10-16) Chanaday, Natali L. ; Cousin, Michael A. ; Milosevic, Ira ; Watanabe, Shigeki ; Morgan, Jennifer R.

Neurotransmission is sustained by endocytosis and refilling of synaptic vesicles (SVs) locally within the presynapse. Until recently, a consensus formed that after exocytosis, SVs are recovered by either fusion pore closure (kiss-and-run) or clathrin-mediated endocytosis directly from the plasma membrane. However, recent data have revealed that SV formation is more complex than previously envisaged. For example, two additional recycling pathways have been discovered, ultrafast endocytosis and activity-dependent bulk endocytosis, in which SVs are regenerated from the internalized membrane and synaptic endosomes. Furthermore, these diverse modes of endocytosis appear to influence both the molecular composition and subsequent physiological role of individual SVs. In addition, previously unknown complexity in SV refilling and reclustering has been revealed. This review presents a modern view of the SV life cycle and discusses how neuronal subtype, physiological temperature, and individual activity patterns can recruit different endocytic modes to generate new SVs and sculpt subsequent presynaptic performance.
Hsc70 ameliorates the vesicle recycling defects caused by excess alpha-synuclein at synapses

(Society for Neuroscience, 2020-01-15) Banks, Susan M. L. ; Medeiros, Audrey T. ; McQuillan, Molly ; Busch, David J. ; Ibarraran-Viniegra, Ana Sofia ; Sousa, Rui ; Lafer, Eileen M. ; Morgan, Jennifer R.

α-Synuclein overexpression and aggregation are linked to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and several other neurodegenerative disorders. In addition to effects in the cell body, α-synuclein accumulation occurs at presynapses where the protein is normally localized. While it is generally agreed that excess α-synuclein impairs synaptic vesicle trafficking, the underlying mechanisms are unknown. We show here that acute introduction of excess human α-synuclein at a classic vertebrate synapse, the lamprey reticulospinal (RS) synapse, selectively impaired the uncoating of clathrin-coated vesicles (CCVs) during synaptic vesicle recycling, leading to an increase in endocytic intermediates and a severe depletion of synaptic vesicles. Furthermore, human α-synuclein and lamprey γ-synuclein both interact in vitro with Hsc70, the chaperone protein that uncoats CCVs at synapses. After introducing excess α-synuclein, Hsc70 availability was reduced at stimulated synapses, suggesting Hsc70 sequestration as a possible mechanism underlying the synaptic vesicle trafficking defects. In support of this hypothesis, increasing the levels of exogenous Hsc70 along with α-synuclein ameliorated the CCV uncoating and vesicle recycling defects. These experiments identify a reduction in Hsc70 availability at synapses, and consequently its function, as the mechanism by which α-synuclein induces synaptic vesicle recycling defects. To our knowledge, this is the first report of a viable chaperone-based strategy for reversing the synaptic vesicle trafficking defects associated with excess α-synuclein, which may be of value for improving synaptic function in PD and other synuclein-linked diseases.
Synuclein regulates synaptic vesicle clustering and docking at a vertebrate synapse

(Frontiers Media, 2021-11-26) Fouke, Kaitlyn E. ; Wegman, M. Elizabeth ; Weber, Sarah A. ; Brady, Emily B. ; Román-Vendrell, Cristina ; Morgan, Jennifer R.

Neurotransmission relies critically on the exocytotic release of neurotransmitters from small synaptic vesicles (SVs) at the active zone. Therefore, it is essential for neurons to maintain an adequate pool of SVs clustered at synapses in order to sustain efficient neurotransmission. It is well established that the phosphoprotein synapsin 1 regulates SV clustering at synapses. Here, we demonstrate that synuclein, another SV-associated protein and synapsin binding partner, also modulates SV clustering at a vertebrate synapse. When acutely introduced to unstimulated lamprey reticulospinal synapses, a pan-synuclein antibody raised against the N-terminal domain of α-synuclein induced a significant loss of SVs at the synapse. Both docked SVs and the distal reserve pool of SVs were depleted, resulting in a loss of total membrane at synapses. In contrast, antibodies against two other abundant SV-associated proteins, synaptic vesicle glycoprotein 2 (SV2) and vesicle-associated membrane protein (VAMP/synaptobrevin), had no effect on the size or distribution of SV clusters. Synuclein perturbation caused a dose-dependent reduction in the number of SVs at synapses. Interestingly, the large SV clusters appeared to disperse into smaller SV clusters, as well as individual SVs. Thus, synuclein regulates clustering of SVs at resting synapses, as well as docking of SVs at the active zone. These findings reveal new roles for synuclein at the synapse and provide critical insights into diseases associated with α-synuclein dysfunction, such as Parkinson’s disease.
Deletion in chromosome 6 spanning alpha-synuclein and multimerin1 loci in the Rab27a/b double knockout mouse

(Nature Research, 2022-06-14) Pattanayak, Rudradip ; Underwood, Rachel ; Crowley, Michael R. ; Crossman, David K. ; Morgan, Jennifer R. ; Yacoubian, Talene A.

We report an incidental 358.5 kb deletion spanning the region encoding for alpha-synuclein (αsyn) and multimerin1 (Mmrn1) in the Rab27a/Rab27b double knockout (DKO) mouse line previously developed by Tolmachova and colleagues in 2007. Western blot and RT-PCR studies revealed lack of αsyn expression at either the mRNA or protein level in Rab27a/b DKO mice. PCR of genomic DNA from Rab27a/b DKO mice demonstrated at least partial deletion of the Snca locus using primers targeted to exon 4 and exon 6. Most genes located in proximity to the Snca locus, including Atoh1, Atoh2, Gm5570, Gm4410, Gm43894, and Grid2, were shown not to be deleted by PCR except for Mmrn1. Using whole genomic sequencing, the complete deletion was mapped to chromosome 6 (60,678,870–61,037,354), a slightly smaller deletion region than that previously reported in the C57BL/6J substrain maintained by Envigo. Electron microscopy of cortex from these mice demonstrates abnormally enlarged synaptic terminals with reduced synaptic vesicle density, suggesting potential interplay between Rab27 isoforms and αsyn, which are all highly expressed at the synaptic terminal. Given this deletion involving several genes, the Rab27a/b DKO mouse line should be used with caution or with appropriate back-crossing to other C57BL/6J mouse substrain lines without this deletion.
Acute increase of α-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation

(American Society for Cell Biology, 2014-10-01) Busch, David J. ; Oliphint, Paul A. ; Walsh, Rylie B. ; Banks, Susan M. L. ; Woods, Wendy S. ; George, Julia M. ; Morgan, Jennifer R.

Parkinson's disease is associated with multiplication of the α-synuclein gene and abnormal accumulation of the protein. In animal models, α-synuclein overexpression broadly impairs synaptic vesicle trafficking. However, the exact steps of the vesicle trafficking pathway affected by excess α-synuclein and the underlying molecular mechanisms remain unknown. Therefore we acutely increased synuclein levels at a vertebrate synapse and performed a detailed ultrastructural analysis of the effects on presynaptic membranes. At stimulated synapses (20 Hz), excess synuclein caused a loss of synaptic vesicles and an expansion of the plasma membrane, indicating an impairment of vesicle recycling. The N-terminal domain (NTD) of synuclein, which folds into an α-helix, was sufficient to reproduce these effects. In contrast, α-synuclein mutants with a disrupted N-terminal α-helix (T6K and A30P) had little effect under identical conditions. Further supporting this model, another α-synuclein mutant (A53T) with a properly folded NTD phenocopied the synaptic vesicle recycling defects observed with wild type. Interestingly, the vesicle recycling defects were not observed when the stimulation frequency was reduced (5 Hz). Thus excess α-synuclein impairs synaptic vesicle recycling evoked during intense stimulation via a mechanism that requires a properly folded N-terminal α-helix.
A role for an Hsp70 nucleotide exchange factor in the regulation of synaptic vesicle endocytosis

(Society for Neuroscience, 2013-05-01) Morgan, Jennifer R. ; Jiang, Jianwen ; Oliphint, Paul A. ; Jin, Suping ; Gimenez, Luis E. ; Busch, David J. ; Foldes, Andrea E. ; Zhuo, Yue ; Sousa, Rui ; Lafer, Eileen M.

Neurotransmission requires a continuously available pool of synaptic vesicles (SVs) that can fuse with the plasma membrane and release their neurotransmitter contents upon stimulation. After fusion, SV membranes and membrane proteins are retrieved from the presynaptic plasma membrane by clathrin-mediated endocytosis. After the internalization of a clathrin-coated vesicle, the vesicle must uncoat to replenish the pool of SVs. Clathrin-coated vesicle uncoating requires ATP and is mediated by the ubiquitous molecular chaperone Hsc70. In vitro, depolymerized clathrin forms a stable complex with Hsc70*ADP. This complex can be dissociated by nucleotide exchange factors (NEFs) that release ADP from Hsc70, allowing ATP to bind and induce disruption of the clathrin:Hsc70 association. Whether NEFs generally play similar roles in vesicle trafficking in vivo and whether they play such roles in SV endocytosis in particular is unknown. To address this question, we used information from recent structural and mechanistic studies of Hsp70:NEF and Hsp70:co-chaperone interactions to design a NEF inhibitor. Using acute perturbations at giant reticulospinal synapses of the sea lamprey (Petromyzon marinus), we found that this NEF inhibitor inhibited SV endocytosis. When this inhibitor was mutated so that it could no longer bind and inhibit Hsp110 (a NEF that we find to be highly abundant in brain cytosol), its ability to inhibit SV endocytosis was eliminated. These observations indicate that the action of a NEF, most likely Hsp110, is normally required during SV trafficking to release clathrin from Hsc70 and make it available for additional rounds of endocytosis.
Effects of excess brain-derived human alpha-synuclein on synaptic vesicle trafficking

(Frontiers Media, 2021-02-04) Román-Vendrell, Cristina ; Medeiros, Audrey T. ; Sanderson, John B. ; Jiang, Haiyang ; Bartels, Tim ; Morgan, Jennifer R.

α-Synuclein is a presynaptic protein that regulates synaptic vesicle trafficking under physiological conditions. However, in several neurodegenerative diseases, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, α-synuclein accumulates throughout the neuron, including at synapses, leading to altered synaptic function, neurotoxicity, and motor, cognitive, and autonomic dysfunction. Neurons typically contain both monomeric and multimeric forms of α-synuclein, and it is generally accepted that disrupting the balance between them promotes aggregation and neurotoxicity. However, it remains unclear how distinct molecular species of α-synuclein affect synapses where α-synuclein is normally expressed. Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric α-synuclein impaired distinct stages of clathrin-mediated synaptic vesicle endocytosis, leading to a loss of synaptic vesicles. Here, we expand this knowledge by investigating the effects of native, physiological α-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically folded multimeric α-synuclein with a minor component of monomeric α-synuclein. After acute introduction of excess brain-derived human α-synuclein, there was a moderate reduction in the synaptic vesicle cluster and an increase in the number of large, atypical vesicles called “cisternae.” In addition, brain-derived α-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone. In contrast to monomeric or dimeric α-synuclein, the brain-derived multimeric α-synuclein did not appear to alter clathrin-mediated synaptic vesicle endocytosis. Taken together, these data suggest that excess brain-derived human α-synuclein impairs intracellular vesicle trafficking and further corroborate the idea that different molecular species of α-synuclein produce distinct trafficking defects at synapses. These findings provide insights into the mechanisms by which excess α-synuclein contributes to synaptic deficits and disease phenotypes.
Activating transcription factor 3 (ATF3) is a highly conserved pro-regenerative transcription factor in the vertebrate nervous system

(Frontiers Media, 2022-03-08) Katz, Hilary R. ; Arcese, Anthony A. ; Bloom, Ona E. ; Morgan, Jennifer R.

The vertebrate nervous system exhibits dramatic variability in regenerative capacity across species and neuronal populations. For example, while the mammalian central nervous system (CNS) is limited in its regenerative capacity, the CNS of many other vertebrates readily regenerates after injury, as does the peripheral nervous system (PNS) of mammals. Comparing molecular responses across species and tissues can therefore provide valuable insights into both conserved and distinct mechanisms of successful regeneration. One gene that is emerging as a conserved pro-regenerative factor across vertebrates is activating transcription factor 3 (ATF3), which has long been associated with tissue trauma. A growing number of studies indicate that ATF3 may actively promote neuronal axon regrowth and regeneration in species ranging from lampreys to mammals. Here, we review data on the structural and functional conservation of ATF3 protein across species. Comparing RNA expression data across species that exhibit different abilities to regenerate their nervous system following traumatic nerve injury reveals that ATF3 is consistently induced in neurons within the first few days after injury. Genetic deletion or knockdown of ATF3 expression has been shown in mouse and zebrafish, respectively, to reduce axon regeneration, while inducing ATF3 promotes axon sprouting, regrowth, or regeneration. Thus, we propose that ATF3 may be an evolutionarily conserved regulator of neuronal regeneration. Identifying downstream effectors of ATF3 will be a critical next step in understanding the molecular basis of vertebrate CNS regeneration.
Impacts of increased α-synuclein on clathrin-mediated endocytosis at synapses : implications for neurodegenerative diseases

(Wolters Kluwer, 2018-04-27) Medeiros, Audrey T. ; Bubacco, Luigi ; Morgan, Jennifer R.

Parkinson's disease (PD) is a neurodegenerative disease that impacts the lives of millions of people worldwide. A pathological hallmark of PD, as well as dementia with Lewy bodies (DLB) and several Alzheimer's disease variants, is the appearance of intracellular inclusions called Lewy bodies, which contain high levels of aggregated α-synuclein. α-Synuclein is a presynaptic protein that normally associates with synaptic vesicle membranes and regulates synaptic vesicle trafficking under physiological conditions (Calo et al., 2016). However, in familial PD, multiplication and several point mutations in the α-synuclein gene (SNCA) ultimately lead to toxic aggregation of the α-synuclein protein and subsequent degeneration of dopaminergic neurons in the substantia nigra, although other brain areas are also affected (Schulz-Schaeffer, 2010).
Chaperone proteins as ameliorators of alpha-synuclein-induced synaptic pathologies: Insights into Parkinson's disease

(Medknow Publications, 2020-11-27) Banks, Susan M. L. ; Medeiros, Audrey T. ; Sousa, Rui ; Lafer, Eileen M. ; Morgan, Jennifer R.

α-Synuclein accumulation causes synaptic vesicle trafficking defects and may underlie neurodegenerative disorders: Neurodegenerative disorders, such as Parkinson’s disease (PD) and other synucleinopathies, impact the lives of millions of patients and their caregivers. Synucleinopathies include PD, dementia with Lewy Bodies (DLB), multiple system atrophy, and several Alzheimer’s Disease variants. They are clinically characterized by intracellular inclusions called Lewy Bodies, which are rich in atypical aggregates of the protein α-synuclein. While dopaminergic neurons in the substantia nigra are particularly susceptible to α-synuclein-induced aggregation and neurodegeneration, glutamatergic neurons in other brain regions (e.g. cortex) are also frequently affected in PD and other synucleinopathies (Schulz-Schaeffer 2010). Several point mutations in the α-synuclein gene (SNCA), as well as duplication/triplication of SNCA, are linked to familial Parkinson’s disease. In animal models, these genetic alterations lead to overexpression and aberrant accumulation of α-synuclein within neurons, and eventually to neurodegeneration. Interestingly, in both animal models and human patients, α-synuclein aggregation often occurs at neuronal synapses and within axons prior to the appearance of larger aggregates (i.e. Lewy bodies) and other signs of neurodegeneration (Schulz-Schaeffer 2010; Volpicelli-Daley et al., 2011). The level of synaptic aggregation of α-synuclein is highly correlated with greater cognitive deficits in PD and DLB patients (Schulz-Schaeffer 2010). Thus, it is essential to understand how excess α-synuclein impacts synapses, as this may represent an early stage in the neurodegenerative disease progression and thus a viable target for therapeutic intervention, particularly with respect to cognitive impairment.
GABA promotes survival and axonal regeneration in identifiable descending neurons after spinal cord injury in larval lampreys

(Nature Publishing Group, 2018-06-28) Romaus-Sanjurjo, Daniel ; Ledo-García, Rocío ; Fernández-López, Blanca ; Hanslik, Kendra ; Morgan, Jennifer R. ; Barreiro-Iglesias, Antón ; Rodicio, María Celina

The poor regenerative capacity of descending neurons is one of the main causes of the lack of recovery after spinal cord injury (SCI). Thus, it is of crucial importance to find ways to promote axonal regeneration. In addition, the prevention of retrograde degeneration leading to the atrophy/death of descending neurons is an obvious prerequisite to activate axonal regeneration. Lampreys show an amazing regenerative capacity after SCI. Recent histological work in lampreys suggested that GABA, which is massively released after a SCI, could promote the survival of descending neurons. Here, we aimed to study if GABA, acting through GABAB receptors, promotes the survival and axonal regeneration of descending neurons of larval sea lampreys after a complete SCI. First, we used in situ hybridization to confirm that identifiable descending neurons of late-stage larvae express the gabab1 subunit of the GABAB receptor. We also observed an acute increase in the expression of this subunit in descending neurons after SCI, which further supported the possible role of GABA and GABAB receptors in promoting the survival and regeneration of these neurons. So, we performed gain and loss of function experiments to confirm this hypothesis. Treatments with GABA and baclofen (GABAB agonist) significantly reduced caspase activation in descending neurons 2 weeks after a complete SCI. Long-term treatments with GABOB (a GABA analogue) and baclofen significantly promoted axonal regeneration of descending neurons after SCI. These data indicate that GABAergic signalling through GABAB receptors promotes the survival and regeneration of descending neurons after SCI. Finally, we used morpholinos against the gabab1 subunit to knockdown the expression of the GABAB receptor in descending neurons. Long-term morpholino treatments caused a significant inhibition of axonal regeneration. This shows that endogenous GABA promotes axonal regeneration after a complete SCI in lampreys by activating GABAB receptors.
Recovery of burrowing behavior after spinal cord injury in the larval sea lamprey

(University of Chicago Press, 2020-10-27) Katz, Hilary R. ; Fouke, Kaitlyn E. ; Losurdo, Nicole A. ; Morgan, Jennifer R.

Following traumatic spinal cord injury, most mammalian species are unable to achieve substantial neuronal regeneration and often experience loss of locomotor function. In contrast, larval sea lampreys (Petromyzon marinus) spontaneously recover normal swimming behaviors by 10–12 weeks post-injury, which is supported by robust regeneration of spinal axons. While recovery of swimming behavior is well established, the lamprey’s ability to recover more complex behaviors, such as burrowing, is unknown. Here we evaluated the lamprey’s ability to burrow into a sand substrate over the typical time course of functional recovery (1–11 weeks post-injury). Compared to uninjured control lampreys, which burrow rapidly and completely, spinal-transected animals did not attempt burrowing until 2 weeks post-injury; and they often did not succeed in fully covering their entire body in the sand. Burrowing behavior gradually improved over post-injury time, with most animals burrowing partially or completely by 9–11 weeks post-injury. Burrowing behavior has two components: the initial component that resembles swimming with propagated body undulations and the final component that pulls the tail under the sand. While the duration of the initial component did not differ between control and spinal-transected animals across the entire recovery period, the duration of the final component in spinal-transected animals was significantly longer at all time points measured. These data indicate that, after spinal cord injury, lampreys are able to recover burrowing behaviors, though some deficits persist.
Highly conserved molecular pathways, including Wnt signaling, promote functional recovery from spinal cord injury in lampreys

(Nature Publishing Group, 2018-01-15) Herman, Paige E. ; Papatheodorou, Angelos ; Bryant, Stephanie A. ; Waterbury, Courtney K. M. ; Herdy, Joseph R. ; Arcese, Anthony A. ; Buxbaum, Joseph D. ; Smith, Jeramiah J. ; Morgan, Jennifer R. ; Bloom, Ona E.

In mammals, spinal cord injury (SCI) leads to dramatic losses in neurons and synaptic connections, and consequently function. Unlike mammals, lampreys are vertebrates that undergo spontaneous regeneration and achieve functional recovery after SCI. Therefore our goal was to determine the complete transcriptional responses that occur after SCI in lampreys and to identify deeply conserved pathways that promote regeneration. We performed RNA-Seq on lamprey spinal cord and brain throughout the course of functional recovery. We describe complex transcriptional responses in the injured spinal cord, and somewhat surprisingly, also in the brain. Transcriptional responses to SCI in lampreys included transcription factor networks that promote peripheral nerve regeneration in mammals such as Atf3 and Jun. Furthermore, a number of highly conserved axon guidance, extracellular matrix, and proliferation genes were also differentially expressed after SCI in lampreys. Strikingly, ~3% of differentially expressed transcripts belonged to the Wnt pathways. These included members of the Wnt and Frizzled gene families, and genes involved in downstream signaling. Pharmacological inhibition of Wnt signaling inhibited functional recovery, confirming a critical role for this pathway. These data indicate that molecular signals present in mammals are also involved in regeneration in lampreys, supporting translational relevance of the model.

Morgan Jennifer R.

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