Jose F. Abisambra, United States of America

University of Florida Neuroscience and CTRND
Dr. Abisambra is an Associate Professor of Neuroscience and member of the Center for Translational Research in Neurodegenerative Disease at the University of Florida. He leads a vibrant research program focused on establishing the molecular mechanisms linking tau and cellular dysfunction in more than 20 neurodegenerative disorders. His program currently focuses on the direct and indirect impact of tau on RNA translation in models of Alzheimer’s disease, fronto-temporal dementia, and mild-repetitive traumatic brain injury. He obtained his PhD in Huntington Potter's Lab and his postdoc in Chad Dickey's Lab at the University of South Florida. In 2013, he opened his lab as an Assistant Prof. at the University of Kentucky and relocated in 2018 to UF as an Associate Professor, where he continues to focus on tau and translation. Over the years, his research has been and continues to be supported by NIH, DoD, VA, the Alzheimer's Association, and CurePSP foundation, among others, as PI and co-I. With this support, Dr. Abisambra’s lab seeks to bring us closer to understanding the molecular mechanisms of tauopathies, and in doing so, develop more effective therapeutic strategies to improve the quality of life of more than 30M individuals suffering from tauopathies worldwide.

Author Of 3 Presentations

ABERRANT TAU-RNA INTERACTIONS DRIVE RIBOSOMAL SELECTIVITY AND CELLULAR DYSFUNCTION

Session Name
Session Type
SYMPOSIUM
Date
12.03.2021, Friday
Session Time
08:00 - 10:00
Room
On Demand Symposia C
Lecture Time
08:30 - 08:45
Session Icon
On-Demand

Abstract

Aims

A fundamental gap in the field is the incomplete identification of the mechanisms by which tau promotes cellular dysfunction. We and others established that pathological tau shifts the translatome yielding a maladaptive response. However, the molecular mechanisms remain unknown. The overall objective of this study is to establish these mechanisms by defining 1) the impact of pathological tau on translation, 2) the components of RNA translation machinery that interact with tau, 3) alterations to ribosomal transport, and 4) how tau shifts ribosomal specificity promoting a maladaptive translatome.

Methods

We used puromycin to detect changes in newly-synthesized (pumocyinylated) proteins in vitro and in vivo. We then coupled puromycin assays with proteomics or microarrays in the brains of rTg4510 tau transgenic mice to identify proteins altered by tauopathy. We validated results in Alzheimer’s brains using WB, RT-PCR, and E-CLIP. We measured changes in neuronal transport with novel RiboTag-IRES-tau constructs. We also defined the region of tau-ribosome interface region. Finally, we measured changes in translation dynamics with RiboSeq.

Results

We determined that tau expression differentially shifts the transcriptome and the proteome and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. One protein altered by tauopathy is ribosomal protein S6. Ribosomal abnormalities were also identified in Alzheimer’s samples.

Conclusions

Our data establish tau as a driver of RNA translation selectivity. Moreover, considering that regulation of protein synthesis is critical to learning and memory, aberrant tau-RNA/RBPs interactions in disease could explain the linkage between virtually every tauopathy and cognitive impairment and memory decline.

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NOVEL THERAPEUTIC TARGETS TO MITIGATE EARLY NEURONAL DYSFUNCTION AND COGNITIVE DEFICITS IN TAUOPATHY

Session Type
SYMPOSIUM
Date
11.03.2021, Thursday
Session Time
08:00 - 09:45
Room
On Demand Symposia D
Lecture Time
08:30 - 08:45
Session Icon
On-Demand

Abstract

Aims

Tauopathies are a group of more than twenty known neurodegenerative disorders that affect millions of people worldwide. There is no cure for tauopathies, and current therapeutic strategies provide limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression.

Methods

We treated tau transgenic mice with a multi-target kinase inhibitor to identify novel targets that contribute to cognitive impairment and putative therapeutic targets.

Results

Treatment significantly ameliorated neuronal function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to compare this model with known changes in AD, to identify protein changes similar to known AD alterations calcium, mitochondrial, and metabolic/bioenergetic pathways as highly vulnerable. This is the first characterization of pathway networks altered in this tauopathic mouse model as well as the networks responsive to multi-target kinase inhibition. These analyses reveal pathways associated with cognitive function across tauopathies. We identified disease proteins that are consistent between the tauopathic mouse and human proteome.

Conclusions

Our results further demonstrate the novel therapeutic potential of diminishing nitroxidative stress and highlight its involvement in driving the early stages of neuronal and cognitive dysfunction found in neurodegeneration. Additionally, we identified four proteins displaying a pathological overlap between mouse models of AD and persons with AD.

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Presenter of 2 Presentations

ABERRANT TAU-RNA INTERACTIONS DRIVE RIBOSOMAL SELECTIVITY AND CELLULAR DYSFUNCTION

Session Name
Session Type
SYMPOSIUM
Date
12.03.2021, Friday
Session Time
08:00 - 10:00
Room
On Demand Symposia C
Lecture Time
08:30 - 08:45
Session Icon
On-Demand

Abstract

Aims

A fundamental gap in the field is the incomplete identification of the mechanisms by which tau promotes cellular dysfunction. We and others established that pathological tau shifts the translatome yielding a maladaptive response. However, the molecular mechanisms remain unknown. The overall objective of this study is to establish these mechanisms by defining 1) the impact of pathological tau on translation, 2) the components of RNA translation machinery that interact with tau, 3) alterations to ribosomal transport, and 4) how tau shifts ribosomal specificity promoting a maladaptive translatome.

Methods

We used puromycin to detect changes in newly-synthesized (pumocyinylated) proteins in vitro and in vivo. We then coupled puromycin assays with proteomics or microarrays in the brains of rTg4510 tau transgenic mice to identify proteins altered by tauopathy. We validated results in Alzheimer’s brains using WB, RT-PCR, and E-CLIP. We measured changes in neuronal transport with novel RiboTag-IRES-tau constructs. We also defined the region of tau-ribosome interface region. Finally, we measured changes in translation dynamics with RiboSeq.

Results

We determined that tau expression differentially shifts the transcriptome and the proteome and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. One protein altered by tauopathy is ribosomal protein S6. Ribosomal abnormalities were also identified in Alzheimer’s samples.

Conclusions

Our data establish tau as a driver of RNA translation selectivity. Moreover, considering that regulation of protein synthesis is critical to learning and memory, aberrant tau-RNA/RBPs interactions in disease could explain the linkage between virtually every tauopathy and cognitive impairment and memory decline.

Hide