Profiles of women in science: Illana Gozes, Professor Emerita of Clinical Biochemistry, Tel Aviv University DOI Open Access
Dana L. Helmreich

European Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 58(2), P. 2431 - 2436

Published: June 28, 2023

We at EJN are proud to introduce Dr. Illana Gozes as the next scientist for our series of Women in Neuroscience. began this bring visibility and recognition superb women scientists working community (Helmreich et al., 2017) (you can find all previous profiles https://onlinelibrary.wiley.com/doi/toc/10.1111/(ISSN)1460-9568.women-in-science). is currently a Professor Emerita Clinical Biochemistry, serving Director Elton Laboratory Molecular Neuroendocrinology Department Human Genetics Faculty Medicine, Sagol School Neuroscience, Adams Super Center Brain Studies Tel Aviv University. At Doug Brenneman Lab, NIH Receiving Teva Prize 1993 With Ph.D. mentor, Uri Littauer earned BSc University (1973) Weizmann Institute Science 1978, completed postdocs MIT (1979–1980) Salk (1981–1982) was senior associate professor (1982–1988) visiting (1989–1990) later Fogarty-Scholar-in-Residence (1995–1996). In 1990, became an (full professor, 1993) Tel-Aviv received her endowed professorial chair 1997 (Lily Avraham Gildor Chair Investigation Growth Factors), which she held until 2019. 2004, laboratory renamed Diana Ziga (Zelman) (Elbaum) Neuroendocrinology. For about decade, charge University, overseeing university-wide brain research, also served President Israel Society She further on Council Higher Education (2016–2022). Currently, directing Israeli Bee Competition, Secretary European Neurochemistry, Ambassador ERA-NET Neuron, Regional Editor Journal Alzheimer's Disease, member Scientific Advisory Board Association Israel, Summer Neuropeptide Meeting Editor-in-Chief A brief description research: Neuronal Plasticity Nerve Cell Protection Disease The lab takes multi-level approach study function, behavior, memory, drug discovery, from molecules cures. Targeting autism schizophrenia well disease related neurodegeneration utilizing multidisciplinary approach, investigates different aspects neuronal plasticity nerve cell protection, molecular, cellular, systems levels. major focus structure transport mechanisms. discovered ADNP (Activity-Dependent Neuroprotective Protein), essential protein formation implicated autism, schizophrenia, disease, cancer. candidate davunetide, short fragment large molecule named NAP (NAPVSIPQ), CP201 AL-108. Her most recent findings delineated publication entitled: “A novel davunetide (NAPVSIPQQ NAPVSIPQE) point mutation causes mild developmental syndrome” (Gozes & Shazman, 2023). EJN: I had pleasure speaking with Prof. September 2022. memorable quote: “We go into science not only work birds bees, but we do want something that will be meaningful humans centuries.” What start your journey become neuroscientist? Gozes: born raised Jerusalem. Life centered around Hebrew academic life best you could get. There were many people my who affiliated so knew firsthand what it meant researcher. My grandfather medic, such, saw patients coming going drew me medical world. father gave microscope when very young, allowing look nature detail. always interested curious understanding its high school, one friends' mother Ph.D., they used speak DNA over lunchtime, completely captured imagination. double helix brain, together, seemed fascinating topics. When studied actually consulted girlfriend ask should do. wanted biology; loved math, question was—should biology or take chemistry physics, then biology. did latter because difficult, rewarding. took physics went biology, excelled math biochemistry. started Weizmann, didn't have neurobiology department head biochemistry department, convinced important he one. Thus, graduated Institute, Feinberg Graduate 1978. thinking gene therapy before any cloned. RNA translation tubulin actin synthesis nuclei 1975; 1977)—it beginning studies molecular neuroscience. Then, accepted post-doc scholarship (originally intended men, knowledge). While MIT, collaboration Harvard Medical School, published first paper single neuron biochemistry, showing multiple forms Sweadner, 1981). developed monoclonal antibodies Barnstable, 1982). After offered continue husband California; thought weather much better there. thus chose Scripps. worked another year half, time cloning, genetic engineering, learning more moved back returned scientist/associate professor. sabbatical (which extended excellent binational summers), am full almost 30 years, now active emerita, director like being woman science? As student, feel much. But example, mentor. looking around, told accepting students, sure doesn't happen today. actual work, said—I'm getting married two months. indicate. And interviewer (deputy thesis mentor) answered—and baby? It uncalled for, joking don't think harm. He might been leave after year. Well, (actually, left long ago stayed!). felt bias post-doc. Mike Moskowitz (Brain winner 2021) immediate supervisor, collegial. really appreciated background hard freedom collaborate scientists. However, get materials equipment lab, warehouse Massachusetts area, kept asked—Are nurse? Here doctor? So immediately out, if woman, assumed certain position. Also, faculty, there quite number men few women. association formed monthly lectures meetings. remember some how participate man's world, infiltrating world club. assistant Nancy Hopkins time, advanced famous documenting gender (Vest, 1999). On personal level, advisors care man woman; colleagues seem care. Regardless, needed excel maybe than you. If done same CV, may taken seriously—and by This sentiment eloquently written Ben Barres (Barres, 2006). highlights career? Discoveries published, honored, future possibility impact human lives. Do favorite paper? great papers (some cited here), vividly fight each those papers, except rare ones complimented excellent/outstanding. compare neurons glia, good techniques isolate glia. found German isolated translated me. resultant seminal discovered, together colleagues, nucleus. Biological Chemistry accepted, no changes comments whatsoever, just little postcard saying 1977). Where neuroscience 20 years on? love molecules. bodily functions governed molecules, (bio) future, intricate driving healthy lives, able solve these terrible diseases facing. Coupled big data solving mysteries genome aid analysis data, holds promise personalized medicine best, paying close attention sex differences raising awareness converging mechanisms development aging. know, puzzle, comes in, however, hopefully understand more, enabling life. One example—ADNP syndrome. Before, children deficits, know caused deficits. Now non-inherited basis considered sporadic delays, biochemical basis. better, heal help live longer biggest scientific enterprise since started? complete sequence advances computer sciences. Any advice young FENS members? job, it's hobby it. you're doing passion. youngsters, it, workers, matter woman. And, place study, places filled joy science. Choose interesting questions, choose right with—your choice mentor important. Would talk things? book? Regarding book, read (and write) mostly science, classics, including Shakespeare, George Bernard Shaw Oscar Wilde, Shakespeare said “All world's stage, merely players” … show must on. share poem. recite “If,” Rudyard Kipling, every line other poem: Road Not Taken, Robert Frost. Like Frost, road travelled by, has made difference. Frost wrote Stopping Woods Snowy Evening “but promises keep miles sleep.” sentiment—I travelling meetings, meeting storming seeing advance front eyes. truly enjoyed Forum 2022 Paris forward bright new future. interview edited length clarity DLH IG. Dana L Helmreich: Investigation; writing—original draft; writing—review editing. inspired Diversity Inclusion Initiative, includes past present members Senior Editorial Team. goal initiative global community, particularly previously poorly represented groups. peer review history article available https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/ejn.16061.

Language: Английский

Current and future therapeutic strategies for Alzheimer’s disease: an overview of drug development bottlenecks DOI Creative Commons
Yong Peng,

Hong Jin,

Ya-hui Xue

et al.

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Aug. 3, 2023

Alzheimer’s disease (AD) is the most common chronic neurodegenerative worldwide. It causes cognitive dysfunction, such as aphasia and agnosia, mental symptoms, behavioral abnormalities; all of which place a significant psychological economic burden on patients’ families. No specific drugs are currently available for treatment AD, current AD only delay onset progression. The pathophysiological basis involves abnormal deposition beta-amyloid protein (Aβ), tau phosphorylation, decreased activity acetylcholine content, glutamate toxicity, autophagy, inflammatory reactions, mitochondria-targeting, multi-targets. US Food Drug Administration (FDA) has approved five clinical use: tacrine, donepezil, carbalatine, galantamine, memantine, lecanemab. We have focused newer that undergone trials, not been successful result excessive side effects or poor efficacy. Although aducanumab received rapid approval from FDA 7 June 2021, its long-term safety tolerability require further monitoring confirmation. In this literature review, we aimed to explore possible mechanisms underlying occurrence development AD. anti-Aβ anti-tau drugs, mitochondria-targeting multi-targets, commercially bottlenecks encountered in drug development, targets therapeutic strategies future development. hope present new concepts methods therapies

Language: Английский

Citations

69

Davunetide sex-dependently boosts memory in prodromal Alzheimer’s disease DOI Creative Commons
Illana Gozes, J.–L. Blatt, Alexandra Lobyntseva

et al.

Translational Psychiatry, Journal Year: 2024, Volume and Issue: 14(1)

Published: Oct. 2, 2024

Language: Английский

Citations

9

Unexpected gender differences in progressive supranuclear palsy reveal efficacy for davunetide in women DOI Creative Commons
Illana Gozes, Guy Shapira, Alexandra Lobyntseva

et al.

Translational Psychiatry, Journal Year: 2023, Volume and Issue: 13(1)

Published: Oct. 16, 2023

Abstract Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-microtubule interaction, as an ideal drug candidate. However, pooling patient data irrespective of sex concluded no efficacy. Here, analyzing sex-dependency in 52 week-long- PSP clinical trial (involving over 200 patients) demonstrated clear baseline differences brain ventricular volumes, secondary endpoint. Dramatic volume-dependent/volume increase correlations were observed 52-week-placebo-treated females ( r = 0.74, P 2.36 –9 ), whereas davunetide-treated (like males) revealed such effects. Assessment primary endpoints, by the Rating Scale (PSPRS) and markedly more so Schwab England Activities Daily Living (SEADL) scale, showed significantly faster deterioration females, starting at week 13 0.01, correlating with most other endpoints 52). Twice daily davunetide treatments slowed female disease progression significant protection according to SEADL scale early 39 weeks 0.008), well bulbar limb motor domains considered PSPRS, including speaking swallowing difficulties caused damage, fine skills, respectably 0.01), weeks. Furthermore, trial, exploratory Geriatric Depression (GDS) correlated placebo group davunetide-mediated females. Female-specific volume corresponded Together slower seen men, results reveal sex-based efficacy differences, demonstrating neuroprotective disease-modifying impact treatment for patients.

Language: Английский

Citations

13

NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms DOI Creative Commons

Maram Ganaiem,

Nina D. Gildor,

Shula Shazman

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(18), P. 2251 - 2251

Published: Sept. 11, 2023

(1) Background: Recently, we showed aberrant nuclear/cytoplasmic boundaries/activity-dependent neuroprotective protein (ADNP) distribution in ADNP-mutated cells. This malformation was corrected upon neuronal differentiation by the ADNP-derived fragment drug candidate NAP (davunetide). Here, investigated mechanism of nuclear protection. (2) Methods: CRISPR/Cas9 DNA-editing established N1E-115 neuroblastoma cell lines that express two different green fluorescent proteins (GFPs)-labeled mutated ADNP variants (p.Tyr718* and p.Ser403*). Cells were exposed to conjugated Cy5, followed live imaging. further characterized using quantitative morphology/immunocytochemistry/RNA quantifications. (3) Results: rapidly distributed cytoplasm also seen nucleus. Furthermore, reduced microtubule content observed lines. In parallel, disrupting microtubules zinc or nocodazole intoxication mimicked mutation phenotypes resulted nuclear-cytoplasmic boundaries, which treatment. No effects noted on levels. Ketamine, used as a control, ineffective, but both ketamine exhibited direct interactions with ADNP, via silico docking. (4) Conclusions: Through microtubule-linked mechanism, localized cytoplasmic compartments, ameliorating ADNP-related deficiencies. These novel findings explain previously published gene expression results broaden (davunetide) utilization research clinical development.

Language: Английский

Citations

11

Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males DOI

Jospeh Levine,

Alexandra Lobyntseva, Shula Shazman

et al.

Journal of Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 74(1)

Published: Jan. 29, 2024

Language: Английский

Citations

4

Intranasal NAP (Davunetide): Neuroprotection and circadian rhythmicity DOI Creative Commons
Artur Galushkin, Illana Gozes

Advanced Drug Delivery Reviews, Journal Year: 2025, Volume and Issue: 220, P. 115573 - 115573

Published: April 4, 2025

In this review we examine the neuroprotective potential of NAP (davunetide), a small peptide derived from Activity-Dependent Neuroprotective Protein (ADNP), in context neurodevelopmental and neurodegenerative disorders. ADNP, protein essential for brain development function, is associated with tauopathy-related diseases, such as Alzheimer's Disease (AD), circadian rhythm regulation. enhances microtubule stability prevents tauopathy. preclinical studies, shows promise improving cognitive performance correcting behavioral deficits different models. Clinical studies on (davunetide) administered via intranasal delivery have demonstrated its safety, favorable bioavailability, efficacy making it viable therapeutic option. pure tauopathy, progressive supranuclear palsy, significantly slowed disease progression women phase II-III clinical trial. Additionally, complex interactions between pathways, regulation extensive compensation upon ADNP deficiency attest to further development. Thus, an example reductionist approach drug delivery, replacing/enhancing critical large ADNP-related pathways including dysregulated microtubules tauopathy bioavailable investigational drug, davunetide.

Language: Английский

Citations

0

Clinical impact and in vitro characterization of ADNP variants in pediatric patients DOI Creative Commons

Chuanhui Ge,

Yuxin Tian, Chunchun Hu

et al.

Molecular Autism, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 22, 2024

Helsmoortel-Van der Aa syndrome (HVDAS) is a rare genetic disorder caused by variants in the activity-dependent neuroprotector homeobox (ADNP) gene; hence, it also called ADNP syndrome. multitasking protein with function as transcription factor, playing critical role brain development. Furthermore, have been identified one of most common single-gene causes autism spectrum (ASD) and intellectual disability. We assembled cohort 15 Chinese pediatric patients, 13 coding region gene, evaluated their clinical phenotypes. Additionally, we constructed corresponding performed western blotting immunofluorescence analysis to examine expression subcellular localization human HEK293T SH-SY5Y cells. Our study conducted thorough characterization manifestations children variants, revealed broad symptoms including global developmental delay, disability, ASD, facial abnormalities, other features. In vitro studies were carried out check variants. Two cases presented missense while remainder exhibited nonsense or frameshift leading truncated mutants overexpression systems. Both overexpressed wildtype all different found be confined nuclei cells; however, distinctive pattern nuclear bodies formed was either partially entirely disrupted mutant proteins. Moreover, two p.Y719* on signal (NLS) pattern, predominantly manifesting cytoplasm limited relatively small sample size absence longitudinal framework monitor progression patient conditions over time. lacked vivo evidence further indicate causal implications reported first HVDAS patients population provided systematic presentations laboratory examinations. multiple validated them vitro. findings offered valuable insights into diverse associated HVDAS.

Language: Английский

Citations

3

From circadian sleep disruption to Neuroprotection: The potential of VIP/PACAP in Alzheimer’s disease treatment DOI Creative Commons
Artur Galushkin, Illana Gozes

Current Research in Biotechnology, Journal Year: 2024, Volume and Issue: 8, P. 100254 - 100254

Published: Jan. 1, 2024

Language: Английский

Citations

3

Protective inherited mutations in activity-dependent neuroprotective protein (ADNP): the good, the bad, and the ugly DOI
Illana Gozes, Shula Shazman, Eliezer Giladi

et al.

Genomic psychiatry :, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 7

Published: Nov. 14, 2024

Activity-dependent neuroprotective protein (ADNP), essential for brain formation/function, reveals multiple cytoplasmic and chromatin interacting sites. Computational modeling, alongside the Vineland Adaptive Behavior Scales, a leading instrument supporting diagnosis of intellectual/developmental disabilities, now revealed protective frame shift/stop mutation in ADNP. Thus, woman with inherited mutation, ADNP_Glu931Glyfs * 12 (VB), showed above average performance. Bioinformatics/ silico modeling indicated that while ADNP contains four 14-3-3 interaction sites (instrumental nuclear/cytoplasmic shuttling), an additional fifth site, implicating stronger associations. Furthermore, endogenous (investigational drug, davunetide) NAPVSIPQ (NAP) site was involved 12-14-3-3 interactions. In this respect, also enhanced ADNP-SH3 associations (another NAPVISP 354-361 aa on ADNP, critical cytoskeletal/cellular signaling). HB, 8-year-old VB's son, inheriting mother's further presented heterozygous pathogenic de novo p.Arg730Thrfs 5. However, comparison to carriers similar p.Arg730 (part autistic/intellectual disability syndrome), HB exhibited overall better 3 standard score 70–80 all measures, compared nominal 20 27-year-old subject 100 ± 15 norm, corroborating protection.

Language: Английский

Citations

3

ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation DOI Creative Commons
Guy Shapira, Gidon Karmon, Gal Hacohen-Kleiman

et al.

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 23, 2024

Abstract Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical neurogenesis cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism somatic parallel Alzheimer’s disease progression. Furthermore, clinical trials with the fragment NAP (the investigational drug davunetide) showed efficacy women suffering from tauopathy progressive supranuclear palsy differentially boosted memory men (spatial) (verbal), exhibiting prodromal disease. While more prevalent boys women, both involve impaired neurogenesis. Here, we asked whether sex-dependently regulates Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, identified two-fold higher labeling hippocampal sub-ventricular zone ADNP-intact male versus female mice. Adnp haplo-insufficient ( +/− ) mice or CRSIPR/Cas9-edited present most neurodevelopmental syndrome mutation, p.Tyr718* (Tyr) dramatic reductions BrdU incorporation, resulting mutated females presenting than males. Treatment compensated reduction labeling. Mechanistically, RNAseq revealed male-specific Tyr down-regulation endoplasmic reticulum unfolded response genes sex-dependent organogenesis. Newly discovered mitochondrial accessibility was inhibited by Tyr718* mutation further revealing female-specific downregulation ATP6 . moderated much differential expression caused p.Tyr718*, accompanied neurotoxic, pro-inflammatory pro-apoptotic genes. Thus, key regulator that acts controlling canonical pathways, compensating fundamental deficiencies, striding toward development targeting related neurodevelopmental/neurodegenerative diseases.

Language: Английский

Citations

3