Restoring the Cellular Cleanup Crew: A Potential New Approach to Neurodegenerative Disease
For years, the prevailing theory in neurodegenerative diseases like alzheimer’s, ALS, and Parkinson’s focused on the buildup of protein aggregates as the primary cause of neuronal damage. However, research led by the Steller lab suggests a different starting point: a breakdown in the delivery of the cell’s protein-degrading machinery, known as proteasomes, to synapses. These vital components are responsible for clearing out damaged proteins, maintaining healthy neuronal communication. When proteasome transport falters, waste accumulates, and synaptic function deteriorates.This viewpoint shifts the focus from simply clearing existing damage to proactively maintaining the cellular cleanup system.
A key protein identified in this transport process is PI31. This protein acts as an adaptor, loading proteasomes onto cellular motors for their journey to synapses and ensuring their proper assembly upon arrival. Studies have shown that without sufficient PI31, proteasome transport is disrupted, leading to protein buildup and the eventual formation of aggregates. Loss-of-function mutations in PI31, and in genes coding for related proteins, have been linked to several neurodegenerative diseases. Notably, genetic variations in the PI31 gene have been observed in patients diagnosed with Alzheimer’s, ALS, and Parkinson’s disease.
Driven by these findings, Steller’s team investigated whether boosting PI31 levels could prevent neurodegeneration, utilizing a model based on the rare genetic disorder caused by mutations in the FBXO7 gene. This disorder results in an early-onset, Parkinson’s-like syndrome in humans, and importantly, FBXO7 levels are directly correlated with PI31 levels – loss of FBXO7 leads to a decrease in PI31.
Initial experiments using fruit fly models mimicking FBXO7 deficiency demonstrated severe motor defects and impaired proteasome transport.Though, introducing extra copies of the PI31 gene reversed these symptoms, restoring proper proteasome movement. These promising results were then replicated in FBXO7-deficient mice. even modest increases in PI31 levels substantially suppressed neuronal degeneration, preserved motor function, and improved overall health. Remarkably,in certain specific cases,the lifespan of these mice was extended nearly fourfold. Furthermore, increased PI31 levels facilitated the clearance of abnormal tau proteins, a characteristic feature of Alzheimer’s disease.
These results strongly suggest that increasing PI31 expression can effectively maintain proteasome transport and prevent the progression of neurodegenerative hallmarks in both flies and mice. Current research is focused on determining whether PI31 can preserve cognitive function in aging mice, paving the way for potential preclinical growth of therapies for humans.
Recent collaborative research from the Steller lab has identified rare human mutations in the PI31 gene associated with a range of neurodegenerative conditions.This discovery suggests that PI31-based therapies could initially target these rare disorders caused by FBXO7 or PI31 deficiency. Steller anticipates that insights gained from treating these conditions could ultimately inform broader strategies for slowing age-related cognitive decline and addressing more prevalent neurodegenerative diseases like Alzheimer’s.
