Proteasome-Activating Drug Reverses Neurodegenerative Disease Symptoms in Mouse Model

Accumulation of insoluble tau protein complexes, which characterizes several types of neurodegenerative diseases, was associated with a decrease in brain proteasome peptidase activity that could be restored by treatment with a phosphodiesterase-4 inhibitor (PDE4 inhibitor) drug.

The ubiquitin-proteasome system (UPS) is the mechanism by which malfunctioning and possibly toxic proteins are removed from the cell. This system is based on the tagging of damaged proteins with ubiquitin and the digestion of the subsequent ubiquitinated proteins by the proteasome.

Investigators at Columbia University (New York, NY, USA) investigated the effects of tau accumulation on proteasome function in a neurodegenerative disease mouse model and in a model that was crossed to a UPS reporter protein mouse (line Ub-G76V-GFP).

They reported in the December 21, 2015, online edition of the journal Nature Medicine that accumulation of insoluble tau was associated with a decrease in the peptidase activity of brain 26S proteasomes and with higher levels of ubiquitinated proteins and intact Ub-G76V-GFP. The 26S proteasomes from the neurodegenerative mice were found to be physically associated with tau and less active in hydrolyzing ubiquitinated proteins, small peptides, and ATP. Furthermore, 26S proteasomes from normal mice incubated with recombinant oligomers or tau fibrils also showed lower hydrolyzing capacity in the same assays, implicating tau as a proteotoxin.

The investigators treated some of the neurodegenerative mice with the drug rolipram, a selective phosphodiesterase-4 inhibitor (PDE4 inhibitor), which had been discontinued after clinical trials showed that its therapeutic window was too narrow; it could not be dosed at high enough levels to be effective without causing significant gastrointestinal side effects. The enzyme PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP, thereby increasing levels of cAMP within cells.

PDE4 inhibitors are known to possess procognitive (including long-term memory-improving), wakefulness-promoting, neuroprotective, and anti-inflammatory effects. Consequently, PDE4 inhibitors have been investigated as treatments for a diverse group of different diseases, including central nervous system disorders.

In the current study, the investigators found that administration of rolipram activated cAMP–protein kinase A (PKA) signaling and led to attenuation of proteasome dysfunction, probably through proteasome subunit phosphorylation. This led to lower levels of aggregated tau and improvements in cognitive performance in the mice.

“We have identified a new way to activate the brain’s garbage disposal system, and have shown that we can effectively use a drug to activate this system and slow down disease in a mouse model,” said senior author Dr. Karen E. Duff, professor of pathology and cell biology at Columbia University. “This has the potential to open up new avenues of treatment for Alzheimer’s and many other neurodegenerative diseases. Even though much work has been done, we still do not know exactly which form of a particular protein is toxic to the brain. This has made it difficult to develop drugs to treat neurodegenerative diseases. In Alzheimer’s disease, the problem is compounded because several types of abnormal protein can accumulate in a person’s brain, including amyloid, tau, alpha-synuclein, and TDP43. We think that a well-functioning proteasome will be able to clear out everything at once.”

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