scholarly journals Farnesyl Transferase Inhibition for the Treatment of Tauopathies

2018 ◽  
Author(s):  
Israel Hernandez ◽  
Gabriel Luna ◽  
Jennifer N Rauch ◽  
Michel Giroux ◽  
Celeste M Karch ◽  
...  
Keyword(s):  
Tau Protein ◽  
Direct Reduction ◽  
Protein A ◽  
Protective Mechanism ◽  
Regulatory Pathway ◽  
Tau Pathology ◽  
Post Translational Modifications ◽  
Farnesyl Transferase ◽  
Behavioral Abnormalities ◽  
Farnesyl Transferase Inhibitor

Tau inclusions are a shared feature of many neurodegenerative conditions and tau mutations lead to frontotemporal dementia. Approaches to treatment of these conditions have focused directly on the tau protein by targeting its post-translational modifications, its levels and its tendency to aggregate. We discovered a novel regulatory pathway for tau degradation that operates through the Rhes protein, a GTPase. Rhes is farnesylated and treatment with the farnesyl transferase inhibitor, lonafarnib, reduced Rhes, attenuated behavioral abnormalities, significantly reduced atrophy, tau inclusions, sumoylation and ubiquitination, as well as microgliosis in the rTg4510 tauopathy mouse. Direct reduction of Rhes levels reproduced the results observed with lonafarnib. The mechanism of lonafarnib action, as mediated by Rhes to reduce tau pathology, operates through the lysosome without involvement of the proteasome. Finally we show that the developmental increase in Rhes levels can be homeostatically regulated in the presence of tau mutations as a protective mechanism through which cells sense abnormal tau before any pathology is present. The extensive human trials of lonafarnib for other conditions, makes this drug ideal for repurposing to treat tauopathies.

scholarly journals A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy

2019 ◽  
Vol 11 (485) ◽  
pp. eaat3005 ◽  
Author(s):  
Israel Hernandez ◽  
Gabriel Luna ◽  
Jennifer N. Rauch ◽  
Surya A. Reis ◽  
Michel Giroux ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Posttranslational Modifications ◽  
Direct Reduction ◽  
Induced Pluripotent Stem Cell ◽  
Tau Proteins ◽  
Tau Pathology ◽  
Farnesyltransferase Inhibitor ◽  
Rtg4510 Mouse ◽  
Behavioral Abnormalities ◽  
Farnesylated Protein

Tau inclusions are a shared feature of many neurodegenerative diseases, among them frontotemporal dementia caused by tau mutations. Treatment approaches for these conditions include targeting posttranslational modifications of tau proteins, maintaining a steady-state amount of tau, and preventing its tendency to aggregate. We discovered a new regulatory pathway for tau degradation that operates through the farnesylated protein, Rhes, a GTPase in the Ras family. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib reduced Rhes and decreased brain atrophy, tau inclusions, tau sumoylation, and tau ubiquitination in the rTg4510 mouse model of tauopathy. In addition, lonafarnib treatment attenuated behavioral abnormalities in rTg4510 mice and reduced microgliosis in mouse brain. Direct reduction of Rhes in the rTg4510 mouse by siRNA reproduced the results observed with lonafarnib treatment. The mechanism of lonafarnib action mediated by Rhes to reduce tau pathology was shown to operate through activation of lysosomes. We finally showed in mouse brain and in human induced pluripotent stem cell–derived neurons a normal developmental increase in Rhes that was initially suppressed by tau mutations. The known safety of lonafarnib revealed in human clinical trials for cancer suggests that this drug could be repurposed for treating tauopathies.

scholarly journals BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology

2021 ◽  
Vol 9 (2) ◽  
pp. 77
Author(s):  
Sandra Caecilie Signore ◽  
Fred Silvester Wouters ◽  
Matthias Schmitz ◽  
Mathias Baehr ◽  
Pawel Kermer
Keyword(s):  
Tau Protein ◽  
Crucial Role ◽  
Protein A ◽  
Tau Pathology

scholarly journals Microglia in Alzheimer’s Disease in the Context of Tau Pathology

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1439 ◽  
Author(s):  
Juan Ramón Perea ◽  
Marta Bolós ◽  
Jesús Avila
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Molecular Mechanisms ◽  
Senile Plaques ◽  
Protein A ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Tau Pathology ◽  
The Impact

Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.

scholarly journals Insoluble Tau From Human FTDP-17 Cases Exhibit Unique Transmission Properties In Vivo

2020 ◽  
Vol 79 (9) ◽  
pp. 941-949
Author(s):  
Sarah A Weitzman ◽  
Sneha Narasimhan ◽  
Zhuohao He ◽  
Lakshmi Changolkar ◽  
Jennifer D McBride ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Tau Protein ◽  
Protein A ◽  
Chromosome 17 ◽  
Intracellular Accumulation ◽  
Tau Pathology ◽  
Clinical Presentations ◽  
Hyperphosphorylated Tau Protein ◽  
Human Brains

Abstract One hallmark of neurodegenerative diseases is the intracellular accumulation of hyperphosphorylated tau protein, a neuronal microtubule-associated protein, into structures known as neurofibrillary tangles. Tauopathies are heterogeneous neurodegenerative diseases caused by the misfolding of the tau protein. It has been previously shown that the tau protein can spread from cell to cell in a prion-like manner. Tauopathies can be sporadic or familial, with the identification of pathogenic mutations in the microtubule-associated protein tau gene on chromosome 17 in the familial cases. Different frontotemporal dementia with parkinsonism-17 (FTDP-17) cases are associated with varying clinical presentations and types of neuropathology. We previously demonstrated that insoluble tau extracted from sporadic tauopathy human brains contain distinct tau strains, which underlie the heterogeneity of these diseases. Furthermore, these tau strains seeded tau aggregates that resemble human tau neuropathology in nontransgenic and 6hTau mice in vivo. Here, we show insoluble tau from human brains of FTDP-17 cases transmit different patterns of neuronal and glial tau pathology in vivo, similar to the sporadic tauopathies. This suggests that each of these tau mutations has unique properties that underlie the heterogeneity of FTDP-17 cases.

scholarly journals Molecular Processing of Tau Protein in Progressive Supranuclear Palsy: Neuronal and Glial Degeneration

2021 ◽  
Vol 79 (4) ◽  
pp. 1517-1531
Author(s):  
Alejandra Martínez-Maldonado ◽  
Miguel Ángel Ontiveros-Torres ◽  
Charles R. Harrington ◽  
José Francisco Montiel-Sosa ◽  
Raúl García-Tapia Prandiz ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Glial Cells ◽  
Conformational Changes ◽  
Tau Protein ◽  
Paired Helical Filaments ◽  
Phosphorylated Tau ◽  
Clinical Heterogeneity ◽  
Post Translational Modifications ◽  
Binding Domains ◽  
Tau Isoforms

Background: Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) are examples of neurodegenerative diseases, characterized by abnormal tau inclusions, that are called tauopathies. AD is characterized by highly insoluble paired helical filaments (PHFs) composed of tau with abnormal post-translational modifications. PSP is a neurodegenerative disease with pathological and clinical heterogeneity. There are six tau isoforms expressed in the adult human brain, with repeated microtubule-binding domains of three (3R) or four (4R) repeats. In AD, the 4R:3R ratio is 1:1. In PSP, the 4R isoform predominates. The lesions in PSP brains contain phosphorylated tau aggregates in both neurons and glial cells. Objective: Our objective was to evaluate and compare the processing of pathological tau in PSP and AD. Methods: Double and triple immunofluorescent labeling with antibodies to specific post-translational tau modifications (phosphorylation, truncation, and conformational changes) and thiazin red (TR) staining were carried out and analyzed by confocal microscopy. Results: Our results showed that PSP was characterized by phosphorylated tau in neurofibrillary tangles (NFTs) and glial cells. Tau truncated at either Glu391 or Asp421 was not observed. Extracellular NFTs (eNFTs) and glial cells in PSP exhibited a strong affinity for TR in the absence of intact or phosphorylated tau. Conclusion: Phosphorylated tau was as abundant in PSP as in AD. The development of eNFTs from both glial cells and neuronal bodies suggests that truncated tau species, different from those observed in AD, could be present in PSP. Additional studies on truncated tau within PSP lesions could improve our understanding of the pathological processing of tau and help identify a discriminatory biomarker for AD and PSP.

scholarly journals Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1916
Author(s):  
Ziad Omran ◽  
Mahmood H. Dalhat ◽  
Omeima Abdullah ◽  
Mohammed Kaleem ◽  
Salman Hosawi ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Protein A ◽  
P53 Gene ◽  
Cancer Therapies ◽  
Transactivation Domain ◽  
P53 Family ◽  
Post Translational Modifications ◽  
P53 Status ◽  
Apoptotic Effects ◽  
High Degree

The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as oncogenes. The TAp73 protein has a high degree of similarity with both p53 function and structure, and it induces the regulation of various genes involved in the cell cycle and apoptosis. Unlike those of the p53 gene, the mutations in the p73 gene are very rare in tumors. Cancer cells have developed several mechanisms to inhibit the activity and/or expression of p73, from the hypermethylation of its promoter to the modulation of the ratio between its pro- and anti-apoptotic isoforms. The p73 protein is also decorated by a panel of post-translational modifications, including phosphorylation, acetylation, ubiquitin proteasomal pathway modifications, and small ubiquitin-related modifier (SUMO)ylation, that regulate its transcriptional activity, subcellular localization, and stability. These modifications orchestrate the multiple anti-proliferative and pro-apoptotic functions of TAp73, thereby offering multiple promising candidates for targeted anti-cancer therapies. In this review, we summarize the current knowledge of the different pathways implicated in the regulation of TAp73 at the post-translational level. This review also highlights the growing importance of targeting the post-translational modifications of TAp73 as a promising antitumor strategy, regardless of p53 status.

scholarly journals The Farnesyl Transferase Inhibitor (FTI) SCH66336 (lonafarnib) Inhibits Rheb Farnesylation and mTOR Signaling

2005 ◽  
Vol 280 (35) ◽  
pp. 31101-31108 ◽  
Author(s):  
Andrea D. Basso ◽  
Asra Mirza ◽  
Gongjie Liu ◽  
Brian J. Long ◽  
W. Robert Bishop ◽  
...  
Keyword(s):  
Mtor Signaling ◽  
Farnesyl Transferase ◽  
Farnesyl Transferase Inhibitor

AADVAC1, AN ACTIVE IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE AND NON ALZHEIMER TAUOPATHIES: AN OVERVIEW OF PRECLINICAL AND CLINICAL DEVELOPMENT

2018 ◽  
pp. 1-7
Author(s):  
P. Novak ◽  
N. Zilka ◽  
M. Zilkova ◽  
B. Kovacech ◽  
R. Skrabana ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Phase 1 ◽  
Primary Progressive Aphasia ◽  
Tau Proteins ◽  
Active Immunotherapy ◽  
Tau Pathology

Neurofibrillary tau protein pathology is closely associated with the progression and phenotype of cognitive decline in Alzheimer’s disease and other tauopathies, and a high-priority target for disease-modifying therapies. Herein, we provide an overview of the development of AADvac1, an active immunotherapy against tau pathology, and tau epitopes that are potential targets for immunotherapy. The vaccine leads to the production of antibodies that target conformational epitopes in the microtubule-binding region of tau, with the aim to prevent tau aggregation and spreading of pathology, and promote tau clearance. The therapeutic potential of the vaccine was evaluated in transgenic rats and mice expressing truncated, non mutant tau protein, which faithfully replicate of human tau pathology. Treatment with AADvac1 resulted in reduction of neurofibrillary pathology and insoluble tau in their brains, and amelioration of their deleterious phenotype. The vaccine was highly immunogenic in humans, inducing production of IgG antibodies against the tau peptide in 29/30 treated elderly patients with mild-to-moderate Alzheimer’s. These antibodies were able to recognise insoluble tau proteins in Alzheimer patients’ brains. Treatment with AADvac1 proved to be remarkably safe, with injection site reactions being the only adverse event tied to treatment. AADvac1 is currently being investigated in a phase 2 study in Alzheimer’s disease, and a phase 1 study in non-fluent primary progressive aphasia, a neurodegenerative disorder with a high tau pathology component.

Heteronemin as a Protein Farnesyl Transferase Inhibitor

2004 ◽  
Vol 42 (6) ◽  
pp. 454-456 ◽  
Author(s):  
Véronique Ledroit ◽  
Cécile Debitus ◽  
Frédéric Ausseil ◽  
Roselyne Raux ◽  
Jean-Louis Menou ◽  
...  
Keyword(s):  
Farnesyl Transferase ◽  
Protein Farnesyl Transferase ◽  
Farnesyl Transferase Inhibitor

scholarly journals Synergistic effect of farnesyl transferase inhibitor lonafarnib combined with chemotherapeutic agents against the growth of hepatocellular carcinoma cells

Oncotarget ◽  
2017 ◽  
Vol 8 (62) ◽  
pp. 105047-105060 ◽  
Author(s):  
Jialiang Wang ◽  
Yifan Lian ◽  
Yurong Gu ◽  
Hongbo Wang ◽  
Lin Gu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Synergistic Effect ◽  
Chemotherapeutic Agents ◽  
Carcinoma Cells ◽  
Hepatocellular Carcinoma Cells ◽  
Farnesyl Transferase ◽  
Farnesyl Transferase Inhibitor
Sign in / Sign up

Export Citation Format

Share Document