Proteasomal Failure as a Contributing Cause of Protein Aggregation in Neurodegenerative Disease

Neurodegenerative diseases are characterized by the formation of protein aggregates, misfolded proteins that encourage other molecules of the same protein to also misfold in the same way, forming solid deposits that damage and destroy brain cells. Researchers here suggest that the age-related decline in proteasomal function is a contributing factor. The proteasome is a structure that breaks down damaged or otherwise unwanted proteins in cells. While this form of cellular housekeeping does decline with age, and there is good evidence in lower animals for increased proteasomal function to slow aging, it is worth bearing in mind that the research here is based on deliberately breaking proteasomes by removing a crucial component protein. It is always difficult to say whether the results of this sort of breakage are relevant to aging - it strongly depends on the details in each case.

Proteasomes are made in the cell body of a neuron and need to be transported over long distances to reach the nerve endings where the neuron connects with other cells - a journey of more than one meter in some cases. When proteasomes fail to reach these critical communication hubs, the cell descends into turmoil. Instead of being degraded, damaged proteins in these sites hang around long enough to interact with other binding partners, form aggregates, and disrupt cell function. Over time, this causes degeneration of nerve fibers and ultimately cell death.

When researchers began investigating the proteasome transportation system in fruit flies, they identified a protein called PI31, which plays a crucial role in loading the proteasomes onto the cellular components that ferry them around. They show that PI31 enhances binding and promotes movement of proteasomes with cellular motors. Without it, transport is halted. This is the case in both fly and mouse neurons, suggesting that the transport mechanism is common between many species. Digging deeper into what happens when PI31 is defective, the scientists generated mice whose PI31 gene was switched off in two groups of brain cells with particularly long extensions. They found that without PI31, proteasomes cannot travel, resulting in abnormal protein levels at the tips of neuronal branches. The PI31-lacking neurons also looked peculiar, both with respect to their branches and to their synapses, the structures where branches from two neurons connect. Notably, these structural changes became progressively more severe with age.

There are other reasons to suspect that the lab's findings could inform the treatment of neurodegenerative diseases. For example, mutations in the PI31 gene have been linked to Alzheimer's disease. The fact that PI31 appears to be involved in the early stages of nerve cell degeneration is especially compelling, as it could mean that drugs blocking this protein might have the potential to halt brain damage early on in the process. The researchers believe the formation of aggregates is likely not the direct disease mechanism, but rather a symptom of bigger problems. "Our work suggests that it really starts with a local defect in proteasomes, resulting in the failure to degrade proteins that are critical for nerve function. These undigested proteins subsequently form aggregates and activate additional damage control pathways. But eventually, these clearance systems are overwhelmed, which causes a slow but steady progression to a detectable disease."



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