The accumulation of misfolded tau protein into tangles is a key feature of Alzheimer’s disease (AD). Normally, cells have an efficient system called proteostasis that marks and removes misfolded and dysfunctional proteins, but this process doesn’t work the way it should in AD. Therapeutic approaches targeting individual proteostasis pathways have shown limited success. Some researchers believe that the solution isn’t fixing one pathway at a time but rather boosting the entire system as a whole. A collaborative team of Dr. Xu Chen (UCSD) and Dr. Bokai Zhu (U Pitt) recently identified a potential target called nuclear speckles that could significantly influence the entire proteostasis system in AD neurons.
Nuclear speckles are structures within the cell’s nucleus that appear as small spots when viewed under a microscope. These speckles play an important role in regulating gene expression by controlling which genes are turned on or off. The team discovered that these speckles act as key hubs for proteostasis. A structural protein called SON provides support within these speckles and helps maintain their organization and function. Importantly, they found that SON levels are reduced in AD, other tauopathies, and during normal aging. This reduction leads to fewer nuclear speckles and impaired function. When SON expression was increased experimentally, both the number and function of nuclear speckles were restored. This restoration enhanced the expression of genes involved in proteostasis and reduced the accumulation of protein aggregates.
The team identified an FDA-approved drug, pyrvinium pamoate (PP), as a nuclear speckle rejuvenator that directly acts on SON to enhance proteostasis and decrease tau pathology. They hypothesize that boosting nuclear speckle activity through increased SON function could strengthen the entire proteostasis network and potentially delay or even reverse tau-mediated neurodegeneration in AD.
Dr. Chen’s lab will test this hypothesis through two experimental aims. In the first, they will test PP’s ability to prevent and/or counteract tau pathology and cognitive deficits in two mouse models: one with tau pathology and one with amyloid and tau pathology. They will also determine optimal drug dosing and assess the potential side effects and safety profile for this use of PP. In the second aim, they will test a second method for increasing SON expression: AAV-mediated gene therapy. This approach uses a harmless virus to deliver new genetic material into specific cells, where the cell machinery then translates it into proteins. The team will use this gene therapy to produce more of a segment of the SON protein where PP binds. The second aim of this grant will test whether this gene therapy can reduce tauopathy both alone and in combination with PP. The idea is that since PP activity seems to rely on binding to SON, having more SON fragments available for binding should enhance PP activity. They will test this in the same mouse models described above. The Chen lab will evaluate the short- and long-term effectiveness of each therapy to determine whether the therapies are more useful as a prevention or a cure.
