Fly on the Wall

Making fly science approachable for everyone

Tag: Parkinson’s disease

Breaking research: A study in fruit flies finds a possible drug target to compensate for symptoms of Parkinson’s disease

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.

Cartoon of mitochondrial maintainanceFigure 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 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.

Cartoon of balance between PINK1/Parkin and MUL1Figure 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 Yun et al, 2014







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


  • Yun J., Huan Yang, Michael A Lizzio, Chunlai Wu, Zu-Hang Sheng & Ming Guo (2014). MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin, eLife, 3 DOI:
  • Diedrich M., Grit Nebrich, Andrea Koppelstaetter, Jie Shen, Claus Zabel, Joachim Klose & Lei Mao (2011). Brain region specific mitophagy capacity could contribute to selective neuronal vulnerability in Parkinson’s disease, Proteome Science, 9 (1) 59. DOI:

Translational Findings: How fruit flies are helping us understand Parkinson’s disease

Parkinson’s disease is the second most common neurodegenerative disorder, and patients experience primarily movement-related symptoms including shaking and rigidity in their limbs, slow movements, and difficulty walking, all of which progressively worsen over time. It was formally recognized as a disease in 18171, but didn’t receive much attention until it was given its name in 1861. Parkinson’s disease was not very well understood, and there were no real treatments for about 100 years. Then, in the 1960s researchers discovered that Parkinson’s patients had low levels of dopamine, a chemical in the brain that some neurons use for communication. This finding led to the use of L-Dopa (also known as levodopa) as a treatment. L-Dopa is taken orally and can reach the brain, where it is converted to dopamine2. Now approximately 40 years later, L-Dopa is still the primary treatment for Parkinson’s disease.

Cartoon of dopamine loss in Parkinson's diseaseFigure 1. Parkinson’s patients show a decrease in dopamine levels in the brain. source

The problem is that L-Dopa doesn’t work forever. Since the 1960s, we have learned that Parkinson’s disease is caused by progressive damage and eventual loss of dopaminergic (DA) neurons (these are the ones that release the dopamine), most severely in an area of the brain important for movement known as the basal ganglia3. As more and more DA neurons become damaged and die off, L-Dopa loses its ability to compensate and the symptoms start to come back.  To make matters worse, L-Dopa has a number of side effects that need to be treated with yet more drugs. Of course, L-Dopa is currently very necessary for treating Parkinson’s disease and can give patients an extra 5-15 years of quality symptom-free life. Even as L-Dopa’s effectiveness begins to decrease, it’s still better than no treatment at all. But newer and better treatments need to be developed.

Unfortunately, we can’t fix the disease until we understand what’s causing it. Why are the DA neurons dying? How can we stop it and then reverse the damage? We’ve learned just about everything we can from (ethical) research in humans. It’s time to bring in the model animals! The humble fruit fly Drosophila melanogaster has emerged as a particularly important model because while most cases of Parkinson’s disease occur randomly, about 10-15% of cases are due to inherited genetic mutations. And for genetic research, flies are our best bet.

Why study the genetic mutations if only 10-15% of cases are caused by them? The easiest answer is because we can introduce mutations into the same genes in fruit flies to find out what those genes do. If researchers can figure out what’s causing damage to the DA neurons in the genetic cases, those findings can be directly applied to the random cases. So even if we don’t yet know what caused them,  treatments that protect DA neurons and compensate for their damage should still work to improve symptoms in both genetic and random cases of Parkinson’s disease.

Since the late 1990s, mutations in five genes have been found to lead to inherited forms of Parkinson’s disease in some families. Each was given a cryptic name: SNCA4, Parkin5, PINK16, DJ-17, and LRRK28-9. Once those genes were identified in human patients, researchers were able to mutate the same genes in animal models to figure out what they do and how their failure leads to Parkinson’s disease. Luckily for us, fruit flies already have four of those genes, so it was relatively easy to make a fly line with a mutation in them.  The remaining gene, SNCA, can still be studied by introducing the human mutation into flies using a binary expression system (UAS/GAL4).

Magnified image of Lewy body in brain of Parkinson's patientFigure 2. alpha-synuclein proteins clump to form masses called Lewy bodies. Figure depicts magnified image of a Lewy body surrounded by neurons in the substantia nigra (a part of the basal ganglia) in a patient with Parkinson’s disease. Photo by Suraj Rajan / CC BY-SA 3.0

So what have we learned so far from our winged friends?  An overview of fruit fly research for each gene is listed below, but if you just want the punchline, here it is: Parkin, PINK1, DJ-1, and LRRK2 are all involved in maintaining and/or protecting mitochondria, which are structures inside cells that create the fuel the cell uses as energy (think of them as little power plants). When any of these four genes is mutated, mitochondria begin to function abnormally and are more sensitive to damage from environmental stressors such as toxins. As more and more damage accumulates, DA neurons begin to die off, which may explain why Parkinson’s disease is progressive and usually begins later in life. On the other hand, although the role of normal SNCA is still unknown, a mutated SNCA gene creates masses in the brain called Lewy bodies that may cause damage to DA neurons. Although it’s not fully understood why mutations in these genes affect DA neurons more severely than other neurons in the brain, it is thought that DA neurons may simply be more sensitive to environmental toxins.

Okay, but what about the random cases?  While the cause of most of the random cases of Parkinson’s disease remains a mystery, results from research in the genetic cases can give us a clue. It is currently thought that this form of Parkinson’s disease is caused by a combination of factors such as accumulated damage and genetic mutations with age, exposure to environmental toxins such as pesticides, and genetic predisposition (meaning that there may be genes that don’t directly cause Parkinson’s disease, but may increase your risk if exposed to certain environmental triggers).

Research in fruit flies has definitely improved our understanding of the underlying causes of Parkinson’s disease, which will ultimately lead to the development of better treatments. Instead of simply compensating for reduced dopamine levels, future treatments may target the Lewy bodies or bolster the cell’s protective mechanisms for mitochondria. Treatments such as these will have longer lasting effects because they could potentially prevent further loss of DA neurons. And fruit flies aren’t our only hope. Many of the findings described above have already been used for designing studies in mammalian models, and research in mammals has also led to important discoveries not mentioned here.


Findings in fruit flies specific to each Parkinson-related gene:

  • Parkin/PINK1: I grouped these two mutations together because fruit fly researchers have recently discovered that these genes play similar roles in neurons10-12. PINK1’s protein actually interacts with Parkin’s protein to maintain and protect mitochondria. As a result, a mutation in either PINK1 or Parkin causes mitochondrial defects and increases sensitivity to environmental stress from toxins. The accumulation of damage leads to death in DA neurons and, of course, the resulting impairments in movement as seen in Parkinson’s patients. Further understanding of how PINK1 and Parkin work will allow researchers to develop drugs to compensate for lost function in these genes.
  • SNCA: Many Parkinson’s patients develop dense masses in their brains called Lewy bodies, which are formed when large molecules called proteins accumulate abnormally and bind to each other. Lewy bodies are primarily made up of the protein alpha-synuclein bound to various other proteins (alpha-synuclein is made from the instructions in the SNCA gene). But why is alpha-synuclein clumping together? Researchers introduced the mutated version of the human SNCA gene in fruit flies and found that mutant flies showed progressive DA neuron death and loss of motor skills, just like the symptoms in human Parkinson’s patients13. And of course, they found clumps of protein. Studies in this fly model are now focused on understanding why the mutated version of alpha-synuclein clump together and cause DA neuron death. Once these questions have been answered, researchers can develop treatments that either prevent formation of Lewy bodies, break them down, or prevent them from damaging neurons. Interestingly, researchers have found that when they add extra normal PINK1 or Parkin protein in this SNCA mutant, the extra PINK1 or Parkin actually helps to protect against DA neuron death14-15. So, another treatment option for Parkinson’s patients with Lewy bodies may be to stimulate extra PINK1 or Parkin protein production as a protective measure.
  • DJ-1:  Researchers have found that fruit flies with a mutation in DJ-1β (flies actually have two versions of this gene, and DJ-1β is similar to the human version) are more sensitive to environmental toxins, demonstrating that this gene plays a protective role16. Flies with this mutant gene also showed reduced lifespan and locomotor defects, as seen in Parkinson’s patients17. Finally, mutant DJ-1 protein resulted in abnormal mitochondrial function, suggesting that this gene, like PINK1 and Parkin, is necessary for normal functioning in mitochondria18.
  • LRRK2: Mutations in LRRK2 are likely the most common genetic cause of Parkinson’s disease in humans, but it has so far been the most inconsistent in fruit flies, making it a difficult gene to study. Researchers have performed several kinds of genetic manipulations, including completely knocking-out LRRK2 function, introducing the mutated version of the human gene, or mutating it in a way that changed its function instead of making it completely non-functional. Some researchers found that the mutations led to DA neuron death and severely impaired movement, some researchers found no effect, and others found a result somewhere in the middle19. A few important reliable discoveries have come out of research in this gene, however. First, all of the mutants were more sensitive to various environmental toxins. Second, researchers found that LRRK2 proteins interact with mitochondria, suggesting that it, like PINK1 and Parkin, plays a role in maintaining and/or protecting these structures. These findings support an increasingly convincing conclusion that Parkinson’s disease may be caused by mitochondrial defects or damage that leads to death in DA neurons.


Interested in recent Parkinson’s disease research in fruit flies? Check out the Breaking Research post on MUL1.



  1. Parkinson J. (1817). An Essay on the Shaking Palsy, Journal of Neuropsychiatry, 2002, 14 (2) 223-236. DOI:
  2. <Cotzias G.C. (1967). Dopa and Parkinsonism, BMJ, 3 (5563) 497-497. DOI:
  3. Blandini F., Cristina Tassorelli & Emilia Martignoni (2000). Functional changes of the basal ganglia circuitry in Parkinson’s disease, Progress in Neurobiology, 62 (1) 63-88. DOI:
  4. <Polymeropoulos M.H. (1997). Mutation in the -Synuclein Gene Identified in Families with Parkinson’s Disease, Science, 276 (5321) 2045-2047. DOI:
  5. Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., Yokochi M., Mizuno Y. & Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism., Nature, PMID:
  6. Valente E.M. (2004). Hereditary Early-Onset Parkinson’s Disease Caused by Mutations in PINK1, Science, 304 (5674) 1158-1160. DOI:
  7. Bonifati V. (2003). Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism, Science, 299 (5604) 256-259. DOI:
  8. Paisán-Ruı́z C., E.Whitney Evans, William P. Gilks, Javier Simón, Marcel van der Brug, Adolfo López de Munain, Silvia Aparicio, Angel Martı́nez Gil, Naheed Khan & Janel Johnson & (2004). Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson’s Disease, Neuron, 44 (4) 595-600. DOI:
  9. Zimprich A., Petra Leitner, Peter Lichtner, Matthew Farrer, Sarah Lincoln, Jennifer Kachergus, Mary Hulihan, Ryan J. Uitti, Donald B. Calne & A.Jon Stoessl & (2004). Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology, Neuron, 44 (4) 601-607. DOI:
  10. Clark I.E., Changan Jiang, Joseph H. Cao, Jun R. Huh, Jae Hong Seol, Soon Ji Yoo, Bruce A. Hay & Ming Guo (2006). Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin, Nature, 441 (7097) 1162-1166. DOI:
  11. Park J., Sungkyu Lee, Yongsung Kim, Saera Song, Sunhong Kim, Eunkyung Bae, Jaeseob Kim, Minho Shong, Jin-Man Kim & Jongkyeong Chung & (2006). Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin, Nature, 441 (7097) 1157-1161. DOI:
  12. Yang Y., Y. Imai, Z. Huang, Y. Ouyang, J.-W. Wang, L. Yang, M. F. Beal, H. Vogel & B. Lu (2006). Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin, Proceedings of the National Academy of Sciences, 103 (28) 10793-10798. DOI:
  13. Feany M.B. & Bender W.W. A Drosophila model of Parkinson’s disease., Nature, PMID:
  14. Bell J. & Brian E. Staveley (2008). Pink1 suppresses α-synuclein -induced phenotypes in a Drosophila model of Parkinson’s disease , Genome, 51 (12) 1040-1046. DOI:
  15. Haywood A.F.M. & Staveley B.E. (2004). Parkin counteracts symptoms in a Drosophila model of Parkinson’s disease., BMC neuroscience, PMID:
  16. Yang Y., Md. E. Haque, Y. Imai, J. Kosek, L. Yang, M. F. Beal, I. Nishimura, K. Wakamatsu, S. Ito & R. Takahashi & (2005). Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling, Proceedings of the National Academy of Sciences, 102 (38) 13670-13675. DOI:
  17. Meulener M., Cecilia E. Armstrong-Gold, Patrizia Rizzu, Peter Heutink, Paul D. Wes, Leo J. Pallanck & Nancy M. Bonini (2005). Drosophila DJ-1 Mutants Are Selectively Sensitive to Environmental Toxins Associated with Parkinson’s Disease, Current Biology, 15 (17) 1572-1577. DOI:
  18. Hao L.Y. & N. M. Bonini (2010). DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function, Proceedings of the National Academy of Sciences, 107 (21) 9747-9752. DOI:
  19. Muñoz-Soriano V. (2011). Drosophila Models of Parkinson’s Disease: Discovering Relevant Pathways and Novel Therapeutic Strategies, Parkinson’s Disease, 2011 1-14. DOI:


General references and reviews:

© 2023 Fly on the Wall

Theme by Anders NorenUp ↑

Protected by Akismet
Blog with WordPress

Welcome Guest | Login (Brandeis Members Only)