Faulty transportation mechanisms within nerve cells may lead to neurodegeneration in Alzheimer's or Parkinson's disease.
The ability to take apart proteins that are damaged, the wrong shape, or surplus to requirements is a crucial function in living cells. This process occurs at specific locations within the cell.
Some of these locations can be more than 1 meter from the cell body in neurons, or nerve cells because they lie along their axons, which are long thin fibers that link them to other neurons.
Cells use complex molecular machines called proteasomes to break down proteins at their specific sites of activity.
One of the hallmarks of neurodegenerative disease is the buildup of proteins that have failed to break down.
Examples include the accumulation of beta-amyloid in Alzheimer's and alpha-synuclein in Parkinson's disease.
As undegraded proteins accumulate, they stick to each other and other substances, clogging up brain cells and disrupting their function. The cells eventually stop working and die.
The new research, carried out by scientists at Rockefeller University in New York, NY, supports the idea that failure to transport proteasomes could be a cause of the protein buildup that occurs in neurodegenerative disease.
"This is the first study to find a mechanism by which the proteasomes are moved to nerve endings to do their job," says Prof. Hermann Steller, who is a senior author on both studies.
"When this mechanism gets disrupted," he adds, "there are severe consequences for the function and long-term survival of nerve cells."
In the first study, he and his colleagues investigated proteasomes in fruit flies and mice. There, they found that the protein proteasome inhibitor 31 (PI31) is essential for transporting proteasomes in the axons of neurons.
It appears that PI31 helps proteasomes to couple to the molecular motors that ferry them along, and it also promotes the movement of the motors. Without PI31, proteasome transportation ceases.
Gene manipulation sheds more light
In the second study, the researchers investigated PI31 more thoroughly by manipulating its gene.
They engineered mice with silent PI31 genes in two types of brain cells that have long axons.
With the gene switched off, those cells could not produce PI31 protein and transport proteasomes.
The scientists saw how this led to a buildup of abnormal proteins at the ends of the long axons, or "the distal tips of neurons."
They also saw that neurons with missing PI31 looked odd.
The "structural defects" were particularly noticeable at the branches of axons and at synapses, which form the junctions between neurons.
"Notably, these structural changes became progressively more severe with age," Prof. Steller remarks.
He explains that when they observed the mice with those defects, it reminded them of "the severe behavioral and anatomical defects we see in some human neurogenerative disease."
Potential for new treatments
The researchers believe that their findings will add to growing knowledge about the role of PI31 in neurodegenerative diseases.
For instance, there is a severe type of Parkinson's that strikes earlier in life than other types because of a mutation in the PARK15 gene.
Scientists have proposed that because PARK15 interacts with PI31, its disruption may interfere with proteasome activity.
The researchers are already exploring how to use PI31 and molecules that it interacts with as drug targets.
They hope that it could lead to treatments that intervene early in the disease process since PI31 is active during the early formation of nerve cells.
Another avenue that they are pursuing is how to get halted proteasome transport moving again.
Although the new research focuses on the mechanisms of protein buildup, Prof. Steller does not believe that it is a root cause but more a symptom of something bigger that is happening.
"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."
Prof. Hermann Steller