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Tip60: A realistic target to treat Alzheimer’s disease?

  • Alzheimer’s disease (AD) is the most common brain disease affecting older people.
  • Dr Felice Elefant, a professor at Drexel University in Philadelphia, USA, and her PhD student Akanksha Bhatnagar uncovered that the levels of an enzyme called Tip60 are depleted in the brain of Alzheimer’s patients, negatively affecting production of diverse protein variants.
  • Their research shows that increasing Tip60 has a beneficiary effect by restoring neuronal protein diversity needed for learning and memory.
  • As a potential therapeutic approach, the team will test small molecules designed to enhance Tip60’s enzyme activity.

Alzheimer’s disease (AD) is an incurable disease that affects cognitive function. The greatest risk factor for developing AD is ageing – most people with Alzheimer’s are over 65 years old. AD is a progressive condition that affects parts of the brain that control thought, memory, and language. The main features of Alzheimer’s pathology include the loss of connections between neurons and protein aggregates called amyloid plaques, which are found in the patient’s brain.

Over the years, extensive research on AD has increased our understanding of the pathology of this devastating condition, although insights on the cause of the disease and treatment options lag behind. One important finding is that the protein-making machinery goes awry in AD. Examining this further, a team of researchers at Drexel University and the University of Pennsylvania, USA, uncovered the role of an enzyme called Tip60. Tip60 normally plays a significant role in producing the right kind of proteins for a healthy brain, but it malfunctions in the brain of Alzheimer’s patients.

Protein production goes wrong in Alzheimer’s

Professor Felice Elefant and her PhD student, Akanksha Bhatnagar, at Drexel University in the USA revealed that the levels of the enzyme Tip60 are depleted in Alzheimer’s patients’ brains, which may contribute towards the disease and its progression.

Tip60 has been shown to have a histone acetyltransferase (HAT) activity, meaning that it binds to DNA-wrapping proteins to turn genes on and activate protein production. However, the team uncovered for the first time an unprecedented dual role for Tip60: it also binds certain RNAs in the brain to regulate which types of proteins arise from them.

The levels of enzyme Tip60 are depleted in Alzheimer’s patients’ brains, which may contribute towards the disease and its progression.

DNA contains genes which encode the sequence of all proteins produced in our body. Gene activation is a process tightly regulated within cells to ensure that the right genes are switched on in the correct cell types and stages. This process is particularly important in the brain, given that it contains more than 3,000 different cell types. RNA, which is derived from DNA, is ultimately converted into proteins through a process called translation. The mechanisms that control which genes are activated and when, and which RNA variants will generate proteins, are described with the general term ‘epigenetics’.

Alternative RNA splicing, for example, allows for more than one protein to be derived from a single gene. This is the critical process whereby specific protein variants are produced from RNA to create the protein diversity within a cell necessary to support its functional needs. Brain cells are continuously responding to environmental stimuli and rewiring to allow new memories to be created. These specialised neurons especially rely on RNA splicing to support their complex functions and to generate the protein variants needed for neuroplasticity (structural changes or adaptions in the brain in response to stimuli), which is required for learning and memory processes.

Elefant’s lab had previously shown that the classical HAT property of Tip60 is negatively affected in the brains of AD patients, leading to certain neuronal genes getting inactivated. Using a fly experimental AD model that displays classic features of human AD pathology, they demonstrated that increasing Tip60 reduces neuronal death, restores memory, and promotes neuronal functions.

Tip60 malfunction alters protein diversity in the AD brain

Taking their discoveries further, the team demonstrated in their most recent publication in the renowned Journal of Neuroscience that Tip60 is not only binding DNA-wrapping proteins to activate gene expression in the brains of AD patients. It is also involved in the regulation of RNA alternative splicing (Figure 1). These findings suggest that the altered levels of Tip60 on AD brains affect not only gene activation but also the generation of diverse protein variants.

Figure 1: Polytene chromosome staining showing Tip60 localises to the DNA regions that are actively being transcribed into RNA.
From: Bhatnagar, A, et al, (2023), doi.org/10.1523/JNEUROSCI.2331-22.2023
Figure 2: Tip60 chromodomain protein structure showing the four amino acids in red predicted to aid in Tip60-RNA interactions.
From: Bhatnagar, A, et al, (2023), doi.org/10.1523/JNEUROSCI.2331-22.2023

Using the same fly experimental AD model, Elefant and Bhatnagar show that malfunction of Tip60 is a key cause of AD, as the malfunctioning Tip60 fails to make essential proteins for neuronal function and for cognition. The team also showed that Tip60 has a similar function in the human brain (Figure 2). Indeed, by analysing human samples the researchers observed that Tip60-RNA targeting is also disrupted in the brain of people suffering from Alzheimer’s – particularly in the hippocampus, which is the region that controls memory and is mostly affected during the course of the disease.

Tip60 with its newly discovered role in regulating diverse protein variants may prove a realistic target to treat Alzheimer’s disease.

What’s even more interesting is that when Tip60 levels are brought back to normal, the disease pathology is relieved, suggesting that increasing Tip60 levels can be a potential therapeutic approach for Alzheimer’s. The researchers state: ‘We speculate that such Tip60-RNA binding disruptions ultimately contribute significantly to AD pathologies but can be protected against by increased Tip60 levels.’

Tip60 as a therapeutic target for AD

The next step for Elefant and her team is exploring the potential of Tip60 as a therapeutic target in AD. One way would be to directly enhance Tip60 activity in AD brain which would provide specificity of treatment. The team wants to focus on the HAT activity of Tip60 in gene activation. This would be a powerful selective approach because the AD brain displays reduced Tip60 histone acetylation leading to inactivation of critical synaptic plasticity genes and causing cognitive deficits. To achieve this, the team needs to further discriminate between the two functions of the enzyme and enhance its histone acetyltransferase activity (Figure 3).

Figure 3: Tip60 HAT activation as a unique therapeutic strategy for restoring histone acetylation homeostasis mediated cognition in Alzheimer’s disease.

With a computational drug design approach, Elefant and her colleagues designed and synthesised a novel set of small molecule compounds that can selectively activate Tip60 and promote its histone acetyltransferase activity. These novel compounds will be tested for therapeutic effectiveness in an Alzheimer’s disease model. Tip60 with its newly discovered roles in mediating gene activation and RNA/protein diversity in the brain may prove a realistic target to treat Alzheimer’s disease.

What have been the major challenges hindering progress in finding novel therapies for AD?

Current epigenetic therapies aiming to restore histone acetylation have been shown to be promising in reversing cognitive deficits, but their therapeutic use is limited due to their non-specific mode of action. Importantly, in addition to gene repression, AD brains are also a hotbed for alternative RNA splicing defects, suggesting that solely restoring gene expression may not be adequate for treating AD. Here, we overcome these challenges by a) designing small molecular activators with high specificity towards Tip60 that is expected to give rise to less side effects, and b) discovering a novel RNA-targeting and splicing function for Tip60 that is unprecedented for any histone acetyltransferase enzyme. Together, we propose a ‘one target, two functions’ paradigm in which small molecule activation of Tip60 may have the potential to restore gene expression as well as alternative RNA splicing in the AD brain.

Why did you decide to explore the acetyltransferase activity of Tip60 over its RNA splicing function to explore its therapeutic potential in AD?

We strongly believe that Tip60’s histone acetyltransferase and RNA splicing function are co-dependent such that modulating one function may also have an impact on the other function. Although the precise mechanism by which Tip60 targets RNA has yet to be determined, the huge overlap between Tip60’s gene targets at the chromatin and RNA level is suggestive of Tip60-RNA targeting occurring near its chromatin gene target sites. Thus, Tip60’s specificity towards pre-mRNA may arise from its close proximity to the newly transcribed transcript. Once a gene is activated by Tip60 at the chromatin level for transcription, Tip60 may switch to the newly made pre-mRNA strand and regulate its splicing. In this scenario, although we designed the Tip60 small molecule activators to enhance Tip60 HAT action, concomitant increased gene activation and transcription may also enhance its RNA-targeting and splicing function. An ongoing project in the lab is to dissect the dual functions of Tip60 by mutating either the histone acetylation site, the RNA-binding site, or both sites to study the biological consequences of disrupting these separate functions.

Is RNA the next big thing in neurodegenerative diseases?

Absolutely! RNA splicing brings yet another layer of complexity to solving the neurodegenerative disease puzzle since a person that has no harmful genetic mutations may still develop disease due to defects in RNA alternative splicing mechanisms that do not yield the correct protein variants required for healthy brain function. Indeed, defects in RNA splicing have recently emerged as a widespread mechanism in multiple neurodegenerative diseases and several treatment strategies aiming to restore RNA splicing have been approved by FDA for rare diseases. We are excited to continue the journey to explore the potential of Tip60 mediated RNA splicing-switching therapies for treatment of Alzheimer’s disease.

Related posts.

Further reading

Bhatnagar, A, et al, (2023) Tip60’s novel RNA-binding function modulates alternative splicing of pre-mRNA targets implicated in Alzheimer’s disease, The Journal of Neuroscience, 43(13), 2398–2423.

Professor Felice Elefant

Dr Felice Elefant is a professor in the Department of Biology at Drexel University, Philadelphia, USA. Her laboratory focuses on epigenetic mechanisms underlying human neurodegenerative disorders such as Alzheimer’s disease. Her studies lay the groundwork for neuroepigenetic-based therapeutic approaches for early intervention of cognitive disorders.

Dr Akanksha Bhatnagar

Dr Akanksha Bhatnagar obtained her PhD degree from the Department of Biology at Drexel University, Philadelphia, USA. She is currently a post-doctoral fellow at the University of Pennsylvania, Philadelphia, PA. Under the mentorship of Dr Felice Elefant at Drexel, her research uncovered the convergence of epigenetic and RNA splicing mechanisms that are disrupted under Alzheimer’s disease pathology.

Contact Details

e: [email protected]
w: www.elefantlabdrexel.com

Funding

  • National Institutes of Neurological Disorders and Stroke (NINDS): NIH Award Number R01NS095799

Collaborators

  • Dr Elizabeth A Heller, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, USA
  • Dr Sandhya Kortagere, Department of Microbiology & Immunology, Drexel University College of Medicine, USA

Cite this Article

Elefant, F, Bhatnagar, A, (2024) Tip60: A realistic target to treat Alzheimer’s disease? Research Features, 152.
DOI:
10.26904/RF-152-6257908952

Creative Commons Licence

(CC BY-NC-ND 4.0) This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Creative Commons License

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