Portrait of Nadav Weinstock

Nadav I. Weinstock

Department

Neuroscience, Hunter James Kelly Research Institute

Thesis Title

Cell Specific Ablation of GALC and the Pathogenesis of Krabbe Disease

Email

Undergraduate Education

Biological Sciences, University at Buffalo

Thesis Advisor

Krabbe Disease (KD) is characterized by progressive demyelination in the central and peripheral nervous systems (CNS and PNS). KD affects infants and rapidly progresses to clinical decline and death. The only treatment is Hematopoietic Stem Cell Transplantation (HSCT), which has limited efficacy. KD is caused by mutations in GALC, leading to a loss-of-function in the lysosomal enzyme galactosylceramidase (GALC), responsible for the degradation of galactosylceramide and psychosine. Psychosine accumulates in patients with KD and is toxic to myelinating glia in the CNS (oligodendrocytes) and PNS (Schwann cells). Recent data suggest that psychosine toxicity in KD may also target neurons primarily, causing axonal degeneration independent of demyelination. It is also hypothesized that limitations of HSCT for KD may reflect non-rescued PNS myelination, causing paralysis and autonomic dysfunction leading to sudden death. However, the PNS contribution to KD pathogenesis has not been well defined. Similarly, the primary role of KD on neurons, independent of demyelination, is unknown. To explore the role of these cells in KD, we have generated two complementary mouse models that use conditional mutagenesis. The first is a Galc conditional knockout mouse (cKO), in which exon 9 is flanked by two loxP sites. Preliminary data shows that the fully recombined cKO mouse has a lethal demyelinating phenotype, similar to the well-studied Galc mutant mouse, twitcher. By comparing the fully recombined cKO mouse to Schwann cell-specific or neuron-specific Cre mice, we hope to understand the role of these cells in KD pathogenesis. The second is a transgenic mouse that can selectively express human GALC in a Cre-specific fashion (iGALC). iGALC contains a lox-stop-lox cassette in intron 1, which will allow for Cre-driven recombination and subsequent expression of GALC. We will use the iGALC mice to determine the impact of GALC expression in twitcher Schwann cells or neurons. iGALC founders were produced and we are currently validating the transgene’s function. Experimental mice will be characterized for disease progression by clinical, pathological and molecular measures. Our data will provide information on the interplay between glia and neurons in neurodegeneration, a central emerging question in most neurological diseases. In addition, findings from this study will clarify disease mechanisms of KD and the limitations of HSCT, which will allow us to develop better therapies for KD in the future.

Publications

  • Weinstock, N., Wrabetz, L., Feltri, M.L.,Shin, D. Metabolomic profiling reveals biochemical pathways and potential biomarkers associated with the pathogenesis of Krabbe disease. Journal of Neuroscience Research (2016).
  • Kardys A, Weinstock-Guttman B, Dillon M, Masud MW, Weinstock N, Mahfooz N, Lang JK, Weinstock A, Lincoff N, Zivadinov R, Ramanathan M. Cholesterol affects retinal nerve fiber layer thickness in patients with multiple sclerosis with optic neuritis. Eur J Neurol (2013).
  • Baizer, J. S., Weinstock, N., Witelson, S. F., Sherwood, C. C. & Hof, P. R. The nucleus pararaphales in the human, chimpanzee, and macaque monkey. Brain Struct Funct (2013).
  • Baizer, J. S., Manohar, S., Paolone, N. A., Weinstock, N. & Salvi, R. J. Understanding tinnitus: The dorsal cochlear nucleus, organization and plasticity. Brain Res (2012).

Professional/Educational Meetings/Abstracts

  • Weinstock, N., Shin, D., Wrabetz, L., Feltri, M.L. The Contribution of Schwann cells and Neurons to the Pathogenesis of Krabbe Disease. 2016 Glia in Health & Disease, Cold Spring Harbor Laboratory, NY.
  • Weinstock, N., Shin, D., Berti, C., Wrabetz, L., Feltri, M.L. Therapeutic potential of selective GALC expression in the mouse model of Krabbe disease. 2015. Genetic, Genomics and Bioinformatics Research Day. University at Buffalo, Buffalo, NY.
  • Weinstock, N., Ng, J., Baizer, J. S. The cytoarchitecture and neurochemical properties of the human dorsal cochlear nucleus. 2012 Celebration of Student Academic Excellence, University at Buffalo, 2012, Buffalo, NY.
  • Weinstock, N., Witelson, S. F., Sherwood, C. C., Hof, P. R., Baizer, J. S. The nucleus pararaphales in man, monkey and chimpanzee. Society For Neuroscience, 2011, Washington D.C.
  • Weinstock, N., Witelson, S. F., Sherwood, C. C., Hof, P. R., Baizer, J. S. The nucleus pararaphales in man, monkey and chimpanzee. SfN Buffalo Chapter, 2011, Buffalo, NY.

Awards/Honors

  • Dean’s Letter of commendation, 2012-2014
  • Poster Award recipient at Genetics, Genomics and Bioinformatics Research Day, 2015
  • Poster Award recipient at Genetics, Genomics and Bioinformatics Research Day, 2016
  • NIH NINDS F30 Grant, 2016-present
  • APSA/ASCI/AAP Joint Meeting Travel Award - 2017
  • Associate Faculty Member for F1000 Prime, Neuronal & Glial Cell Biology - 2017
  • University at Buffalo 3 Minute Thesis Finalist - 2017
  • American Physician Scientist Association (APSA) – Fundraising Co-Chair – 2017-2018

Medical School Activities

  • Volunteer at lighthouse clinic and other free medical clinics
  • Member of AMA, Student Interest Group in Neurology, Pediatrics Interest Group

Extracurricular Interests

I enjoy travelling and the outdoors, including backpacking, hiking and camping. Most recently I was able to travel to India and the Himalayas for a medical mission trip to set up medical clinics and explore the many different cultures of Northern India. I also enjoy mountain biking and playing squash. I like reading fiction and trying new foods. I especially enjoy hanging out with my friends and relaxing!