Boosting PI31 Shows Promise in Preventing Neurodegeneration
Research led by Dr. Hugo Steller at Rockefeller University suggests that increasing levels of teh protein PI31 can significantly mitigate neurodegeneration in both fruit flies and mice. The findings point to a potential therapeutic strategy focused on improving cellular “cleanup” systems,rather than solely addressing the resulting protein build-up associated with diseases like Alzheimer’s,Parkinson’s,and ALS.
The core issue, as identified by Steller’s work, lies in the transport of proteasomes – cellular structures responsible for breaking down damaged proteins at synapses, crucial for neuronal dialog. When this transport system falters, protein waste accumulates, disrupting communication and leading to neurodegeneration. PI31 plays a vital role in this transport process,acting as an adaptor protein that loads proteasomes onto cellular motors for delivery to synapses and facilitates their assembly upon arrival.
Studies revealed that a lack of PI31 causes transport to stall, leading to protein aggregation and neurodegeneration in both flies and mice.Importantly, genetic variations impacting PI31 levels or function have been identified in patients diagnosed with Alzheimer’s, ALS, and Parkinson’s disease. This observation prompted steller’s team to investigate whether boosting PI31 levels could offer a therapeutic benefit.
To test this, researchers focused on a rare genetic disorder caused by mutations in the FBXO7 gene, which results in an early-onset, Parkinson’s-like syndrome in humans. FBXO7 is directly linked to PI31; loss of FBXO7 leads to a decrease in PI31 levels.
In fruit fly models lacking the FBXO7 equivalent, the team demonstrated that adding extra copies of PI31 reversed motor defects and restored proteasome transport. Similar results were observed in FBXO7-deficient mice. Even modest increases in PI31 levels significantly suppressed neuronal degeneration, preserved motor function, and improved overall health, extending lifespan nearly fourfold in some cases. Furthermore, increased PI31 levels facilitated the clearance of abnormal tau proteins, a characteristic feature of Alzheimer’s disease.
Recent collaborative research highlighted the clinical relevance of these findings,demonstrating that individuals with rare mutations in the human PI31 gene exhibit a range of neurodegenerative conditions. This suggests that PI31-based therapies could initially target these rare disorders caused by FBXO7 or PI31 deficiency.
Steller’s team is now investigating whether increasing PI31 levels can preserve cognitive function in aging mice, with the ultimate goal of developing preclinical therapies for humans.The research suggests that strategies focused on enhancing PI31 function may hold potential for slowing age-related cognitive decline and addressing more prevalent neurodegenerative diseases.
