Parkinson’s disease is caused by the progressive death of neurons important for movement and results in symptoms such as shaking or rigidity in the limbs, slow movements, and difficulty walking. The primary treatment is a drug called L-Dopa, which compensates for the neuron loss but eventually becomes less effective as more and more neurons die off. Uncovering the cause of neuron death is necessary before treatments can be developed to stop it, and research in fruit flies has already begun to advance our understanding of the disease. A new study published in the open-access journal eLife by the Guo lab expands upon this previous work and uncovers a possible treatment option.

Although most cases of Parkinson’s disease have an unknown cause, about 10-15% are genetic. Two of the implicated genes, PINK1 and Parkin, have been well-studied in Drosophila melanogaster. Just as in humans, a mutation in these genes in fruit flies leads to neuron death and the loss of motor skills. But how? Fruit fly research has shown that PINK1 and Parkin maintain mitochondria, the structures inside cells that provide energy (think of them as little power plants). A single cell can have hundreds or even thousands of mitochondria, depending on its energy needs. Over time, mitochondria can become damaged and begin functioning abnormally. These rogue mitochondria must be broken down and replaced with healthy ones before their dysfunctional behavior can cause damage to the cell. This is where the proteins created by the PINK1/Parkin genes come in.

Figure 1. Pink1 latches onto mitochondria to determine whether or not they are healthy. If the mitochondrion is healthy, Pink1 is quickly removed. Otherwise, Pink1 binds to a passing parkin protein, triggering the destruction of the unhealthy mitochondrion. Image modified from Pink1 latches onto mitochondria to determine whether or not they are healthy. If the mitochondrion is healthy, Pink1 is quickly removed. Otherwise, Pink1 binds to a passing parkin protein, triggering the destruction of the unhealthy mitochondrion. Image modified from Diedrich et al, 2011

PINK1’s job is to latch on to the surface of mitochondria and detect whether or not they are functioning normally. If the mitochondrion is fine, PINK1 gets removed and nothing else happens. On the other hand, if the mitochondrion has been damaged, PINK1 stays put and binds to a passing Parkin protein, which triggers the destruction of the offending mitochondrion. As you’ve probably guessed, a mutation in either the PINK1 or Parkin gene results in an accumulation of dysfunctional mitochondria and leads to cell death. This provides some explanation for why neurons are dying in patients in Parkinson’s disease.

PINK1/Parkin also maintain mitochondria in another way. Mitochondria regularly join with each other and then divide again to replenish their numbers. PINK1/Parkin helps to prevent damaged mitochondria from joining with healthy ones by breaking down a protein called mitofusin, which is responsible for joining mitochondria together. Cells with mutations in PINK1/Parkin have too much mitofusin, which means that damaged mitochondria can hurt the healthy ones by joining with them. To make matters worse, the ratio of joins to divisions is tightly controlled, so when the balance is tipped in favor of joining, big clumps of joined mitochondria begin to form.

The researchers in the Guo lab investigated other proteins involved in mitochondrial maintenance, searching for one that could compensate for mutations in PINK1/Parkin by preventing damaged mitochondria from joining with others and restoring the balance between joins and divisions. They turned their attention on MUL1, a protein that had previously been shown to interact with mitofusin. The authors discovered that adding extra MUL1 proteins into cells with a PINK1/Parkin mutation fixed the mitochondrial problems caused by the mutations! Drosophila neurons with a mutation in PINK1/Parkin have clumps of mitochondria, while normal cells show mitochondria evenly spread out. Incredibly, mutant cells with extra MUL1 protein showed a normal spread of mitochondria. Adding extra MUL1 into mutant cells somehow compensated for the PINK1/Parkin mutations and returned the balance between joins and divisions to normal.

How was the extra MUL1 able to reverse the over-joining of mitochondria? The authors answered this question by manipulating and measuring MUL1 and mitofusin levels in a variety of situations. They found that cells with a non-functional mutation in the MUL1 gene had clumps of mitochondria and too much mitofusin, just like in PINK1/Parkin mutants. On the other hand, normal cells with extra MUL1 protein actually had too little mitofusin and mitochondria that were small and fragmented, suggesting that the balance in these cells had shifted toward too much division. With further investigation, the authors realized that MUL1 protein was actually breaking down mitofusin just like Parkin.

So the addition of extra MUL1 protein can compensate for PINK1/Parkin mutations by breaking down the extra mitofusin, thus returning mitofusin levels back to normal and rebalancing the ratio of mitochondrial joins to divisions. But this research was in fruit flies, so how do we know this will be useful for humans? The authors took their research a step further by demonstrating that MUL1 has the same function in mouse neurons and HeLa cells (human cells), and that extra MUL1 in these models still compensates for PINK1/Parkin mutations.

This is a fantastic finding, but unfortunately it doesn’t mean we’re ready to give MUL1 pills to Parkinson’s patients and cure the disease. The authors introduced extra MUL1 proteins genetically using a method called gene overexpression (check out this Wikipedia article on gene expression for more information). Basically, the authors made the cells produce their own extra MUL1, but a possible treatment would require developing and testing a drug that either forces cells to start making more MUL1 or adds MUL1 directly. Second, MUL1 doesn’t play a role in targeting and destroying damaged mitochondria. This means that while extra MUL1 could help to prevent clumps of mitochondria (which would have spread the damage from unhealthy ones faster), it can’t actually remove damaged mitochondria. So this treatment would not be able to completely stop the accumulation of dysfunctional mitochondria. But there is still hope! This option will be better than our current treatments because it could slow the progression of cell death instead of simply compensating for the loss. And in the future, research in this area will build upon these findings to develop an even better drug.

Figure 2. An increase in MUL1 levels can compensate for loss of PINK1/Parkin and maintain normal mitofusin (mfn) levels (A). A loss of either MUL1 (B) or PINK1/Parkin (C) alone causes an increase in mfn levels. Cells with a loss in both PINK1/Parkin and MUL1 show an even greater increase in mfn levels (D). Image modified from An increase in MUL1 levels can compensate for loss of PINK1/Parkin and maintain normal mitofusin (mfn) levels. A loss of either MUL1or PINK1/Parkinalone causes an increase in mfn levels. Cells with a loss in both PINK1/Parkin and MUL1 show an even greater increase in mfn levels. Image modified from Yun et al, 2014

For more information on Parkinson’s disease research in fruit flies, check out the Parkinson’s Translational Findings post.

References: