Patrizia Casaccia

Last updated
Patrizia Casaccia
Born
Giulianova, Italy
Alma materCatholic University of Rome, State University of New York (SUNY) Health and Science Center, Cornell Weill Medical Center
Known forPathogenesis of demyelinating disorders, oligodendrocyte development
Scientific career
FieldsNeuroscience, neuroimmunology, genetics
InstitutionsIcahn School of Medicine at Mount Sinai

Patrizia Casaccia is an Italian neuroscientist who is the Director of the Neuroscience Initiative of the Advanced Science Research Center at the CUNY Graduate Center, as well as a Professor of Neuroscience, Genetics & Genomics, and Neurology at the Icahn School of Medicine at Mount Sinai. Casaccia is a pioneer in the study of myelin. Her research focuses on understanding the neurobiological and neuroimmune mechanisms of multiple sclerosis and to translate findings into treatments. Casaccia co-founded the Center for Glial Biology at Mount Sinai and CUNY and is one of the Directors of the center.

Contents

Early life and education

Casaccia was born in the coastal town of Giulianova in the province of Teramo, Italy. [1] She grew up with her mother, father, and younger brother in Giulianova. [1] Her father was a physician in Giulianova and her brother grew up to pursue a career in medicine as well. [1] Casaccia attended the Scientific High School of Giulianova, where she graduated with the M. Curie Diploma. [1]

Casaccia attended medical school at the Catholic University of Rome, in the Policlinico A. Gemelli. [1] She graduated with honors from medical school and began to pursue her residency in Neurology at Policlinico A. Gemelli in Rome. [1] Two years into her residency, she was inspired by her Neurology professor to study in America to explore prion proteins and neurodegenerative disease. [1]

She pursued her Ph.D. at the State University of New York Health and Science Center in Brooklyn. [2] She first explored the role of the PrPSC protein in scrapie pathogenesis and also innovated new methods of gene transfer in organotypic hippocampal brain slices to explore kainate receptor biology and electrophysiology. [3] Her doctoral thesis explored sleep dysregulation in patients with brain illness. [1] She completed her PhD in Molecular Biology and Neurobiology, and stayed in New York City to pursue postdoctoral research at Weill Cornell Medical Center and at the Skirball Institute for Molecular Medicine. [2]

Casaccia published a first-author Nature paper in 1996 showing that nerve growth factor highly specifically promotes the death of oligodendrocytes but not neurons, oligodendrocyte precursor cells, or astrocytes. [4] She went on to explore oligodendrocyte progenitor cell (OPC) development, discovering that the cyclin-dependent kinase inhibitor p27 is critical to OPC development, such that differentiation in impaired and proliferation continues. [5] In addition to her research on oligodendrocytes, Casaccia studied neurotrophins and their role in cell survival and differentiation in the central nervous system. [6]

Career and research

Casaccia was recruited to Robert Wood Johnson Medical School in 1999. [7] Casaccia started as an assistant professor, and was promoted to associate professor while running a lab that explored the neurobiological basis of demyelinating disorders. [8]

In 2008, Casaccia was recruited to the Icahn School of Medicine at Mount Sinai in New York City. [7] She holds titles as the Professor of Neuroscience, Professor of Genetics and Genomic Science, and Professor of Neurology. [9] In 2016, Casaccia was appointed to Director of the Neuroscience Initiative within the Advanced Science Research Center at the CUNY Graduate Center. [7] At CUNY, Casaccia is Einstein Professor of Biology within the CUNY Graduate Center. [10] In 2017, Casaccia and her colleague Anne Schaefer founded, and now co-direct, the Center for Glial Biology that spans the educational spaces of both Mount Sinai and CUNY. [2]

Casaccia's research program focuses on translation in order to move basic science from her lab into therapeutic approaches in the clinic to help patients with multiple sclerosis (MS) and other neurodegenerative processes. [11] One major area of research in Casaccia's lab is probing the molecular and genetic mechanisms of oligodendrocyte development, myelin formation, and myelin loss. [11] Through analysis of epigenetic changes and transcriptional changes in glial cells, mostly oligodendrocytes, they are able to understand how certain stimuli or environmental influences may lead to disease phenotypes. [11] While probing the basic biology of glial cells, Casaccia's lab also dissects the mechanisms of neurodegeneration in demyelinating disorders, such as MS. [11] She looks at mitochondrial activity in neurons exposed to the cerebrospinal fluid (CSF) of patients with various neurodegenerative disorders, and she also analyses this CSF for insight into therapeutic targets and molecular pathways. [11]

Oligodendrocyte and myelin development

Early into her professorship at Robert Wood Johnson Medical School, Casaccia returned to her postdoctoral findings, exploring the role of p27 in oligodendrocyte differentiation, to understand how myelin development occurs. [12]  She found that p27 regulates the differentiation of oligodendrocytes by modulating transcription of the gene for myelin basic protein. [12] Casaccia found in 2002 that the delicate balance of proapoptotic and antiapoptotic molecules determine the propensity for cell death. [13] The accumulation of proapoptotic molecules throughout development correlates with increased apoptosis, suggesting that manipulating the balance of these pro- and anti- apoptotic molecules could be useful as a strategy to prevent oligodendrocyte death. [13]

Casaccia made her first discovery about the epigenetic regulation of oligodendrocytes in 2003, showing that their process outgrowth, which is critical to proper function and myelination in the brain, is regulated by chromatin modifiers. [14] Casaccia found that male and female sex hormones have the capacity to regulate differentiation and maturation of oligodendrocytes. [15] Casaccia and her colleagues later found a critical transcription factor, Yin Yang 1, in the differentiation of OPCs. [16]

Therapeutic strategies targeting oligodendrocytes and myelin

Casaccia shifted her focus more towards translation after becoming a professor at Icahn School of Medicine. Focusing on demyelinating diseases, Casaccia found that inhibition of p53 leads to decreased oligodendrogliopathy, myelin preservation, and decreased microglial infiltration, serving as a potential future therapeutic target. [17]

Casaccia contributes to the development of a new model of multiple sclerosis pathogenesis that takes into account genetic risk susceptibility and cell-specific epigenetic changes that occur in the immune system and the nervous system. [18] Casaccia and her team turned to a mouse model of social isolation and found that it had impaired myelination. [19] They were able to reverse the demyelination and enhance oligodendrocyte development through the administration of Clemastine, an antimuscarinic. [19] Overall, they showed that enhancing or repairing myelination can act as a therapeutic strategy towards depressive-like social behaviors in mice. [19] Casaccia has also begun to explore how altering the gut microbiota affects patients with relapsing MS. [19] Casaccia and her team exposed rats to the cerebrospinal fluid of patients with multiple sclerosis. [20]  They found increased levels of ceramide in the CSF, and it led to oxidative stress and bioenergetic failure in the neurons of rats exposed to MS CSF. [20]

Subventricular zone neurogenesis

Casaccia also explored the molecular and genetic mechanisms underlying neurogenesis. She has found that both p53 and p27, early found important in the regulation of oligodendrocyte development, modulate proliferation and self-renewal of adult subventricular zone cells. [21]

Awards and honors

Select publications

Related Research Articles

<span class="mw-page-title-main">Myelin</span> Fatty substance that surrounds nerve cell axons to insulate them and increase transmission speed

Myelin is a lipid-rich material that surrounds nerve cell axons to insulate them and increase the rate at which electrical impulses pass along the axon. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, myelin ensheaths the axon segmentally: in general, each axon is encased in multiple long sheaths with short gaps between, called nodes of Ranvier. At the nodes of Ranvier, which are approximately one thousandth of a mm in length, the axon's membrane is bare of myelin.

<span class="mw-page-title-main">Schwann cell</span> Glial cell type

Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.

<span class="mw-page-title-main">Oligodendrocyte</span> Neural cell type

Oligodendrocytes, also known as oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons within the central nervous system (CNS) of jawed vertebrates. Their function is similar to that of Schwann cells, which perform the same task in the peripheral nervous system (PNS). Oligodendrocytes accomplish this by forming the myelin sheath around axons. Unlike Schwann cells, a single oligodendrocyte can extend its processes to cover around 50 axons, with each axon being wrapped in approximately 1 μm of myelin sheath. Furthermore, an oligodendrocyte can provide myelin segments for multiple adjacent axons.

<span class="mw-page-title-main">Demyelinating disease</span> Any neurological disease in which the myelin sheath of neurons is damaged

A demyelinating disease refers to any disease affecting the nervous system where the myelin sheath surrounding neurons is damaged. This damage disrupts the transmission of signals through the affected nerves, resulting in a decrease in their conduction ability. Consequently, this reduction in conduction can lead to deficiencies in sensation, movement, cognition, or other functions depending on the nerves affected.

<span class="mw-page-title-main">Node of Ranvier</span> Gaps between myelin sheaths on the axon of a neuron

In neuroscience and anatomy, nodes of Ranvier, also known as myelin-sheath gaps, occur along a myelinated axon where the axolemma is exposed to the extracellular space. Nodes of Ranvier are uninsulated and highly enriched in ion channels, allowing them to participate in the exchange of ions required to regenerate the action potential. Nerve conduction in myelinated axons is referred to as saltatory conduction due to the manner in which the action potential seems to "jump" from one node to the next along the axon. This results in faster conduction of the action potential.

Oligodendrocyte progenitor cells (OPCs), also known as oligodendrocyte precursor cells, NG2-glia, O2A cells, or polydendrocytes, are a subtype of glia in the central nervous system named for their essential role as precursors to oligodendrocytes. They are typically identified in the human by co-expression of PDGFRA and CSPG4.

<span class="mw-page-title-main">Myelin oligodendrocyte glycoprotein</span>

Myelin oligodendrocyte glycoprotein (MOG) is a glycoprotein believed to be important in the myelination of nerves in the central nervous system (CNS). In humans this protein is encoded by the MOG gene. It is speculated to serve as a necessary "adhesion molecule" to provide structural integrity to the myelin sheath and is known to develop late on the oligodendrocyte.

<span class="mw-page-title-main">Lesional demyelinations of the central nervous system</span>

Multiple sclerosis and other demyelinating diseases of the central nervous system (CNS) produce lesions and glial scars or scleroses. They present different shapes and histological findings according to the underlying condition that produces them.

Remyelination is the process of propagating oligodendrocyte precursor cells to form oligodendrocytes to create new myelin sheaths on demyelinated axons in the CNS. This is a process naturally regulated in the body and tends to be very efficient in a healthy CNS. The process creates a thinner myelin sheath than normal, but it helps to protect the axon from further damage, from overall degeneration, and proves to increase conductance once again. The processes underlying remyelination are under investigation in the hope of finding treatments for demyelinating diseases, such as multiple sclerosis.

Myelinogenesis is the formation and development of myelin sheaths in the nervous system, typically initiated in late prenatal neurodevelopment and continuing throughout postnatal development. Myelinogenesis continues throughout the lifespan to support learning and memory via neural circuit plasticity as well as remyelination following injury. Successful myelination of axons increases action potential speed by enabling saltatory conduction, which is essential for timely signal conduction between spatially separate brain regions, as well as provides metabolic support to neurons.

<span class="mw-page-title-main">OLIG1</span> Protein-coding gene in the species Homo sapiens

Oligodendrocyte transcription factor 1 is a protein that in humans is encoded by the OLIG1 gene.

<span class="mw-page-title-main">LINGO1</span> Protein-coding gene in the species Homo sapiens

Leucine rich repeat and Immunoglobin-like domain-containing protein 1 also known as LINGO-1 is a protein which is encoded by the LINGO1 gene in humans. It belongs to the family of leucine-rich repeat proteins which are known for playing key roles in the biology of the central nervous system. LINGO-1 is a functional component of the Nogo receptor also known as the reticulon 4 receptor.

<span class="mw-page-title-main">Precursor cell</span> Partially differentiated usually unipotent cell

In cell biology, precursor cells—also called blast cells—are partially differentiated, or intermediate, and are sometimes referred to as progenitor cells. A precursor cell is a stem cell with the capacity to differentiate into only one cell type, meaning they are unipotent stem cells. In embryology, precursor cells are a group of cells that later differentiate into one organ. However, progenitor cells are considered multipotent.

<span class="mw-page-title-main">Myelin regulatory factor</span> Mammalian protein found in Homo sapiens

Myelin regulatory factor, also known as myelin gene regulatory factor (MRF), is a protein that in humans is encoded by the MYRF gene.

MOG antibody disease (MOGAD) or MOG antibody-associated encephalomyelitis (MOG-EM) is an inflammatory demyelinating disease of the central nervous system. Serum anti-myelin oligodendrocyte glycoprotein antibodies are present in up to half of patients with an acquired demyelinating syndrome and have been described in association with a range of phenotypic presentations, including acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, and neuromyelitis optica.

<span class="mw-page-title-main">Erin M. Gibson</span> Glial and circadian biologist

Erin M. Gibson is a glial and circadian biologist as well as an assistant professor in the Department of Psychiatry and Behavioral Sciences and the Stanford Center for Sleep Sciences and Medicine at Stanford University. Gibson investigates the role of glial cells in sculpting neural circuits and mechanistically probes how the circadian rhythm modulates glial biology.

Anne Schaefer is a neuroscientist, professor of Neuroscience, vice-chair of Neuroscience, and director of the Center for Glial Biology at the Icahn School of Medicine at Mount Sinai in New York City. Schaefer investigates the epigenetic mechanisms of cellular plasticity and their role in the regulation of microglia-neuron interactions. Her research is aimed at understanding the mechanisms underlying various neuropsychiatric disorders and finding novel ways to target the epigenome therapeutically.

Margaret Ransone Murray was an American scientist known primarily for her work on methods to establish cultures of neuronal cells. Her in vitro studies in cellular neurobiology shed light on both nerve- muscle relationships and axon myelination.

Catherine Lubetzki is a French neurologist who is a professor at Sorbonne University. She is head of the Department of Neurological Diseases at the Pitié-Salpêtrière Hospital, where she coordinates the Salpêtrière Multiple Sclerosis clinical research centre. Her research involves the physiology of multiple sclerosis, and identifying the interactions between myelin and axons. In 2019, she was awarded the Multiple Sclerosis International Federation Charcot Award.

A myelinoid or myelin organoid is a three dimensional in vitro cultured model derived from human pluripotent stem cells (hPSCs) that represents various brain regions, the spinal cord or the peripheral nervous system in early fetal human development. Myelinoids have the capacity to recapitulate aspects of brain developmental processes, microenvironments, cell to cell interaction, structural organization and cellular composition. The differentiating aspect dictating whether an organoid is deemed a cerebral organoid/brain organoid or myelinoid is the presence of myelination and compact myelin formation that is a defining feature of myelinoids. Due to the complex nature of the human brain, there is a need for model systems which can closely mimic complicated biological processes. Myelinoids provide a unique in vitro model through which myelin pathology, neurodegenerative diseases, developmental processes and therapeutic screening can be accomplished.

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  4. ↑ Casaccia-Bonnefil, Patrizia; Carter, Bruce D.; Dobrowsky, Rick T.; Chao, Moses V. (October 1996). "Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75". Nature. 383 (6602): 716–719. Bibcode:1996Natur.383..716C. doi:10.1038/383716a0. ISSN   1476-4687. PMID   8878481. S2CID   4318607.
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  14. ↑ Liu, Aixiao; Muggironi, Michela; Marin‐Husstege, Mireya; Casaccia‐Bonnefil, Patrizia (2003). "Oligodendrocyte process outgrowth in vitro is modulated by epigenetic regulation of cytoskeletal severing proteins". Glia. 44 (3): 264–274. doi:10.1002/glia.10290. ISSN   1098-1136. PMID   14603467. S2CID   6316883.
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  17. ↑ Li, Jiadong; Ghiani, Cristina A.; Kim, Jin Young; Liu, Aixiao; Sandoval, Juan; DeVellis, Jean; Casaccia-Bonnefil, Patrizia (2008-06-11). "Inhibition of p53 Transcriptional Activity: A Potential Target for Future Development of Therapeutic Strategies for Primary Demyelination". Journal of Neuroscience. 28 (24): 6118–6127. doi:10.1523/JNEUROSCI.0184-08.2008. ISSN   0270-6474. PMC   2962898 . PMID   18550754.
  18. ↑ Huynh, Jimmy L.; Casaccia, Patrizia (February 2013). "Epigenetic mechanisms in multiple sclerosis: implications for pathogenesis and treatment". The Lancet. Neurology. 12 (2): 195–206. doi:10.1016/S1474-4422(12)70309-5. ISSN   1474-4465. PMC   3690378 . PMID   23332363.
  19. 1 2 3 4 Liu, Jia; Dupree, Jeffrey L.; Gacias, Mar; Frawley, Rebecca; Sikder, Tamjeed; Naik, Payal; Casaccia, Patrizia (2016-01-20). "Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice". The Journal of Neuroscience. 36 (3): 957–962. doi:10.1523/JNEUROSCI.3608-15.2016. ISSN   1529-2401. PMC   4719024 . PMID   26791223.
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  21. ↑ Gil-Perotin, Sara; Haines, Jeffery D.; Kaur, Jasbir; Marin-Husstege, Mireya; Spinetta, Michael J.; Kim, Kwi-Hye; Duran-Moreno, Maria; Schallert, Timothy; Zindy, Frederique; Roussel, Martine F.; Garcia-Verdugo, Jose M. (October 2011). "Roles of p53 and p27(Kip1) in the regulation of neurogenesis in the murine adult subventricular zone". The European Journal of Neuroscience. 34 (7): 1040–1052. doi:10.1111/j.1460-9568.2011.07836.x. ISSN   1460-9568. PMC   3214596 . PMID   21899604.
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