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Jorge A. Ghiso

Jorge A. Ghiso, PhD

Professor, Department of Pathology

Professor, Department of Psychiatry

Keywords
genetic and biochemical basis of Alzheimer Disease, molecular, cellular, & translational neuroscience
Summary

The lab has a long-standing interest and research experience in the molecular bases of disorders of protein folding, specifically systemic and cerebral amyloidosis of both sporadic and hereditary origin. Over the years, our expertise in protein chemistry, amino acid sequence and proteomic analyses facilitated the development of multiple analytical strategies allowing the dissection of the biochemical composition and biophysical characteristics of amyloid deposits in tissue specimens from human disorders as well as from different animal models, while investigating common molecular mechanisms by which different amyloid subunits produce disease. 

Early work featured the biochemical identification of diverse amyloid subunits linked to systemic and cerebral amyloidosis in humans, among them the complete primary structure of the cystatin C Q68 Icelandic-variant, the first discovered genetic mutation of an amyloid subunit linked to cerebral hemorrhage and stroke. The lab further focused its research to the field of Aβ cerebrovascular amyloidosis and Alzheimer’s disease, reporting the first in vitro creation of Aβ amyloid fibrils, uncovering the existence of a soluble circulating form of Aβ, its blood transport by HDL particles enriched in apo J (clusterin), the role of the blood-brain-barrier in modulating the uptake and clearance of Aβ –both, in vitro and in diverse animal models including rat, mouse, guinea pig, and non-human primates–   as well as the discovery of a systemic pathway of Aβ catabolism with physiological relevance.

Research extended to the contribution of mutations and post-translational modifications to the heterogeneity of amyloid deposits and brain clearance mechanisms and to the study of non-Aβ cerebral amyloidosis, investigating rare disorders that constitute alternative non-Aβ models to assess the molecular basis of neurodegeneration, cell death, and amyloid formation in the brain.  This is the case of two genetic disorders –familial British and Danish dementias– exhibiting clinical and neuropathological phenotypes similar (if not identical) to those of Alzheimer’s disease. Their amyloid deposits, however, are composed of the novel amyloid subunits ABri and ADan, respectively, with a primary structure completely unrelated to the Alzheimer’s Aβ, supporting the role of amyloid in the pathophysiology of these protein folding disorders associated with cognitive impairment.

Current projects in the lab are aiming to i) identify and modulate cell signaling pathways triggered by Aβ oligomers in cerebral cells, work that reported for the first time the engagement of TRAIL death receptors DR4 and DR5 in cells of the cerebral microvasculature and the protective involvement of Nrf2 in counterbalancing oxidative and metabolic damage in neuronal cells; ii) dissect, in different brain cells, the common mitochondrial pathways disrupted by unrelated amyloid subunits and their post-translationally modified proteoforms, with particular interest in the development of novel translational approaches; iii) better understand the brain clearance mechanisms of the multiple Aβ species composing the brain Aβ peptidome, identifying specific changes associated with normal aging as well as those related to specific neurodegenerative conditions; and iv) explore novel pathogenic mechanisms, among them the formation ion-like channels, by which amyloid subunits interact with cell membranes affecting normal cell function and inducing pathogenic cellular responses.

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These focus areas and their associated publications are derived from medical subject headings from PubMed.
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Rostagno, Agueda; Calero, Miguel; Holton, Janice L; Revesz, Tamas; Lashley, Tammaryn; Ghiso, Jorge

Neurobiology of disease. 2021 Jul 21; 158:105452

Alić, Ivan; Goh, Pollyanna A; Murray, Aoife; Portelius, Erik; Gkanatsiou, Eleni; Gough, Gillian; Mok, Kin Y; Koschut, David; Brunmeir, Reinhard; Yeap, Yee Jie; O'Brien, Niamh L; Groet, Jürgen; Shao, Xiaowei; Havlicek, Steven; Dunn, N Ray; Kvartsberg, Hlin; Brinkmalm, Gunnar; Hithersay, Rosalyn; Startin, Carla; Hamburg, Sarah; Phillips, Margaret; Pervushin, Konstantin; Turmaine, Mark; Wallon, David; Rovelet-Lecrux, Anne; Soininen, Hilkka; Volpi, Emanuela; Martin, Joanne E; Foo, Jia Nee; Becker, David L; Rostagno, Agueda; Ghiso, Jorge; Krsnik, Željka; Šimić, Goran; Kostović, Ivica; Mitrečić, Dinko; Francis, Paul T; Blennow, Kaj; Strydom, Andre; Hardy, John; Zetterberg, Henrik; Nižetić, Dean

Molecular psychiatry. 2021 Jul 16;

Zampar, Silvia; Klafki, Hans W; Sritharen, Krishyanthy; Bayer, Thomas A; Wiltfang, Jens; Rostagno, Agueda; Ghiso, Jorge; A Miles, Luke; Wirths, Oliver

Neuropathology & applied neurobiology. 2020 Dec; 46(7):673-685

Parodi-Rullán, Rebecca; Ghiso, Jorge; Cabrera, Erwin; Rostagno, Agueda; Fossati, Silvia

Aging cell. 2020 Nov 06; e13258

Alić, Ivan; Goh, Pollyanna A; Murray, Aoife; Portelius, Erik; Gkanatsiou, Eleni; Gough, Gillian; Mok, Kin Y; Koschut, David; Brunmeir, Reinhard; Yeap, Yee Jie; O'Brien, Niamh L; Groet, Jürgen; Shao, Xiaowei; Havlicek, Steven; Dunn, N Ray; Kvartsberg, Hlin; Brinkmalm, Gunnar; Hithersay, Rosalyn; Startin, Carla; Hamburg, Sarah; Phillips, Margaret; Pervushin, Konstantin; Turmaine, Mark; Wallon, David; Rovelet-Lecrux, Anne; Soininen, Hilkka; Volpi, Emanuela; Martin, Joanne E; Foo, Jia Nee; Becker, David L; Rostagno, Agueda; Ghiso, Jorge; Krsnik, Željka; Šimić, Goran; Kostović, Ivica; Mitrečić, Dinko; Francis, Paul T; Blennow, Kaj; Strydom, Andre; Hardy, John; Zetterberg, Henrik; Nižetić, Dean

Molecular psychiatry. 2020 Jul 10;

Karkisaval, Abhijith G; Rostagno, Agueda; Azimov, Rustam; Ban, Deependra K; Ghiso, Jorge; Kagan, Bruce L; Lal, Ratnesh

Nanomedicine : nanotechnology, biology, & medicine. 2020 Jun 10; 29:102235

Sotolongo, Krystal; Ghiso, Jorge; Rostagno, Agueda

Alzheimer's research & therapy. 2020 Mar 24; 12(1):32

Sotolongo, Krystal; Ghiso, Jorge; Rostagno, Agueda

Alzheimer's research & therapy. 2020 Jan 13; 12(1):13