Tauopathies: A Neurodegenerative Disease

Tauopathies are a spectrum of neurodegenerative diseases defined by their cellular pathology. Their name refers to the protein tau which aggregates pathologically in clumps known as fibrils. Tauopathies encompass familiar neurodegenerative diseases, such as Alzheimer’s, as well as others including frontotemporal dementia (FTD) and Pick’s disease. Another more recently publicized tauopathy is chronic traumatic encephalopathy, a disease that results from repetitive head trauma and has been diagnosed in former NFL players.

Human genetics has helped illustrate that mutant tau “is sufficient to cause neurodegeneration,” says Dr. Li Gan, a tau expert at UCSF/Gladstone Institutes, Additionally, the accumulation of non-mutated tau in other neurodegenerative diseases underscores its importance. However, exactly how tau causes neuronal dysfunction and death is unclear.

“As illustrated in recent work from Dr. Gan’s lab, modifications of tau may heavily influence the protein’s pathogenicity. The Gan group has previously demonstrated that acetylation of tau may play a critical role in its toxicity, showing that Alzheimer’s patients had elevated tau acetylation even preceding accumulation of tau fibrils. Their recent paper published in Nature Medicine serves as a “proof of principle,” says Gan, regarding the potential of targeting tau acetylation in therapies.

Using mass spectroscopy, the authors identified one specific acetylation site on tau, lysine 174 (K174), that is key to tau’s pathological function. The authors showed that in vitro and in vivo this site is critical for tau turnover and accumulation. Excitingly, they also demonstrated that blocking K174 acetylation, by inhibiting the upstream acetylating protein p300, rescued behavioral deficits and neuronal death in a mouse model of tauopathy.

The compound the investigators used to inhibit p300 is salsalate, a non-steroidal anti-inflammatory drug (NSAID) related to aspirin and already shown to be safe in humans. As Gan said, “There is hyperactivation of p300 in AD (Alzheimer’s Disease), so partial inhibition of p300 (may be beneficial to patients).” UCSF has already begun recruiting for a drug trial based on this work in patients suffering from progressive supernuclear palsy, another tauopathy.

However, salsalate is not the perfect drug to treat all tauopathies. It does have “associated [gastrointestinal] bleeding,”said Gan. “But the GI bleeding is not due to its inhibition of p300. If we can modify [salsalate] and make it more potent, it could be an even better drug.” Indeed, the Gan group is working with collaborators to improve upon salsalate, as well as identify other more specific inhibitors of p300.

While the ultimate proof that K174 acetylation is involved in human disease will be a successful drug trial in patients, this work has laid the foundation for potential therapeutics in the ongoing drug trial and in future trials in tauopathies.