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BU Team IDs RNA-Binding Proteins as Potential Alzheimer's Biomarkers

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A research team led by scientists at Boston University has identified several RNA-binding proteins as potential therapeutic targets and biomarkers for neurodegenerative diseases including Alzheimer's.

In a paper published this month in the Journal of Neuroscience, the researchers detailed possible links between development of RNA-binding protein aggregates called stress granules and the progression of various neuropathologies, suggesting a role for these proteins in the development of such disorders, Benjamin Wolozin, a professor in the Department of Pharmacology at Boston University and leader of the study, told ProteoMonitor.

The findings, he said, suggest that the protein aggregates could prove useful as therapeutic targets and as diagnostic and progression biomarkers. Wolozin has filed patents related to the proteins and to therapeutic compounds targeting them and is currently working with proteomics firms NextGen Sciences and Proteome Sciences on mass spec-based assays measuring the proteins.

"I haven't launched a company yet, but I'm at the stage where I would like to start a company related [to the research]," he said. He noted that while the compounds he has developed are primarily for therapeutic purposes, "it's easy to imagine diagnostic material coming out of this [research], too."

In response to cellular stress, RNA-binding proteins aggregate into inclusions called stress granules. Recent research has shown these granules co-localize with structures such as tau tangles that are linked to neurodegenerative disease.

In the Journal of Neuroscience paper, Wolozin and his colleagues set out to characterize the relationship between these stress granules and neuropathology in mouse models of tauopathy and human cases of Alzheimer's disease. They found that patterns of stress granule development varied significantly depending on the RNA-binding protein involved, suggesting, they said, "that these proteins might represent novel [Azheimer's] biomarkers whose expression, aggregation, or posttranslational modifications might reflect distinct elements of the disease process."

The researchers focused primarily on three proteins and their corresponding stress granules: T-cell intracellular antigen-1 (TIA-1); tristetraprolin (TTP); and ras GAP-binding protein (G3BP). They found that TIA-1 granules are strongly associated with tau pathology in Alzheimer's disease; TTP granules are associated with tau pathology in severe cases of the disease; and G3BP is not linked to tau pathology but shows increasing accumulation in neurons as the disease progresses.
I know that's not our style but in this case it makes sense

"At the moment we don't know" how useful the proteins might be as Alzheimer's biomarkers, "but we are pursuing [the question]," Wolozin said.

"The [existing] panels are getting to be pretty good even just using [the classic Alzheimer's biomarkers] phosphotau and amyloid-beta," he said. "But one could imagine that these [proteins] could improve [those panels] further."

"Secondly," he added, "if it turns out that these are upregulated earlier in the disease, as some of them appear to be, then that could increase the sensitivity [of existing tests]."

Wolozin also noted that the stress granules' patterns of co-localization with the tau tangles characteristic of Alzheimer's and other neurodegenerative diseases could provide addition prognostic or diagnostic information.

"You could imagine that since [the researchers demonstrated], at least in mouse [models], TTP [granules] co-localize with tau later than TIA-1 granules, that if you had a probe that could look at the interaction between tau and those things it could tell you something about the stage [of the disease]," he said.

Adding such co-localization data might also improve the specificity of a diagnosis, he said. "If you think of differential diagnosis, there might be many things that could elevate [expression of] these proteins… but you could perhaps differentiate, for example, between a stroke and Alzheimer's disease by whether or not the stress granule [co-localizes] with tau."

Wolozin said he has submitted several grants to develop imaging techniques that could collect such co-localization data. He is also currently researching whether the proteins can be picked up in cerebrospinal fluid, although he noted as a caveat that the majority of them are not secreted and so may be difficult to detect in CSF.

He is investigating the markers for use in diagnosing mild cognitive impairment, as well. "We have tissues [for that work] and so we're looking at that this summer," he said. "My assumption is that [they] should pick it up; it's just a matter of finding the right markers."

Alzheimer's has been a prime area of focus for protein biomarker research. A 2011 report commissioned by Proteome Sciences predicted that protein biomarkers for Alzheimer's disease will represent a cumulative $9 billion market over the next ten years (PM 6/3/2011). In addition to their promise for diagnosis and predicting progression of the disease, early detection and progression biomarkers are also expected to play an increasing role in pharmaceutical research into drugs for the disease, helping with selection of patients for clinical trials and monitoring response to therapy.

Wolozin hasn't been in contact with any pharma firms about the protein's potential usefulness as neurodegenerative disease biomarkers, but, he said, he is working with Proteome Sciences on assays to look at the proteins as part of his own work on their commercial potential as therapeutic targets and biomarkers.

Proteome Sciences will help Wolozin in developing a "biomarker strategy" to aid in the development of the therapeutic compounds targeting the RNA-binding proteins that he aims to commercialize, Glenn Barney, the company's vice president of sales and marketing told ProteoMonitor.

"[Wolozin] is looking to collaborate with us to do the companion diagnostic along with those compounds and looking at biomarkers to enrich their clinical trials and things like that," Barney said.

Wolozin noted that he is also collaborating with mass spec proteomics firm NextGen Sciences on work looking into the proteins' links to Parkinson's disease.

Launching a company to commercialize the IP he's registered around the proteins is his first choice, he said, but, he added, he is also open to the possibility of licensing it to an interested party.

"It's early days," he said. "I'd like to start a company, but that's contingent on investors and things like that – it always depends on the funding."

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