Parkinson's disease

To bring the tools you need for Parkinson’s disease research, we partnered with The Michael J. Fox Foundation (MJFF) to develop rabbit monoclonal antibodies against promising targets.

​​Robust research requires equally robust tools. In the case of understanding disease pathways, such as those in Parkinson’s, this often means antibodies that reliably bind key targets. Unfortunately, many existing antibodies lack sufficient quality control data, are challenging to obtain, or are tied up in convoluted license agreements, restricting their use. 

We want to help the Parkinson’s community to overcome those hurdles. Together with MJFF, we have been generating antibodies and making them widely available to industry as well as academic and non-profit groups to accelerate therapeutic development for Parkinson’s patients.

Over 50 products for Parkinson’s disease research have been produced as part of the MJFF-Abcam collaboration. Of these, 24 are RabMAb^® rabbit monoclonals – market-leading antibodies due to the quality and value that they provide. Between them, these antibodies cover the four key Parkinson’s target groups of LRRK2, SNCA, DJ-1, RAB 8 & 10. We invite you to learn more about Parkinson’s disease, the MJFF and our collaboration, and the antibodies we have developed in order to give you the edge in your research.    

>> Please see here for further information and resources on Parkinson’s disease, to support your research.

Overview

• What is Parkinson’s disease?
• How is The Michael J. Fox Foundation advancing research?
• What happens in the brains of people with Parkinson’s disease?
• What do we know about the causes of Parkinson’s?
• FirePlex seminar with MJFF
• Rabbit monoclonal antibodies for Parkinson’s disease research 

What is Parkinson’s disease?

Parkinson’s is a neurodegenerative condition in which regions of the brain become increasingly more damaged over time. The physical symptoms of Parkinson’s are commonly tremor and reduced movement, but patients can also suffer from depression, balance issues, and problems with sleeping and memory. The disease affects around 6 million people worldwide and, as of yet, there is no known cure.

How is The Michael J. Fox Foundation advancing research?

The Michael J. Fox Foundation is dedicated to finding a cure for Parkinson's disease through an aggressively funded research agenda and to ensuring the development of improved therapies for those living with Parkinson's today.

Learn more about The Michael J. Fox Foundation

What happens in the brains of people with Parkinson’s disease?

The hallmark pathologies of Parkinson’s include the loss of dopaminergic neurons from the pars compacta, a portion of the substantia nigra in the midbrain, which results in slowness of movement (bradykinesia), resting tremor and rigidity¹. Another hallmark of Parkinson’s is intracellular protein aggregates known as Lewy bodies.

Dopaminergic neurons produce the neurotransmitter dopamine, which is responsible for coordinating movement. When these neurons are lost, there is a reduction of dopamine, causing the characteristic motor symptoms of Parkinson’s disease. Motor symptoms normally emerge after the loss of the majority of dopaminergic neurons.

Lewy bodies form when misfolded alpha-synuclein protein aggregates into oligomers, forming β-sheet-rich fibrils. Misfolded alpha-synuclein can move between neurons in a prion-like fashion², where it can act as a template to promote misfolding of normal alpha-synuclein. The accumulation of alpha-synuclein and other proteins is hypothesized to occur before neuronal loss³.

Despite Lewy bodies occurring in regions of neuronal loss, it has been difficult to establish whether their presence correlates with cell death. It is unclear whether Lewy bodies are protective or neurotoxic. However, evidence from multiphoton imaging in mice shows selective death of Lewy body-containing neurons⁴, indicating that their presence is tightly correlated with cellular toxicity and therefore likely to be a pathologically relevant event in the development of Parkinson’s.

What do we know about the causes of Parkinson’s?

The majority of Parkinson’s cases are sporadic, with less than 10% having a genetic component⁵. Contributors to Parkinson's disease include oxidative stress and abnormal protein aggregation and degradation.

Genetics

Mutations in six genes (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP 13A2) are known to contribute to the development of Parkinson’s^6,7. Polymorphisms in three genes (MAPT, LRRK2, and SNCA) and loss-of-function mutations in GBA are also risk factors⁶.

Protein aggregation and misfolding

Aggregation and misfolding of alpha-synuclein are believed to be steps in the development of Parkinson’s disease⁸. Misfolded alpha-synuclein impairs protein caretaking systems, such as the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP). Without these pathways working normally, there is a feedback loop in which alpha-synuclein accumulates, further suppressing UPS or ALP function, leading to neuronal death^9,10,11.

The transcription factor Lmx1b was shown to be essential for normal ALP function and the integrity and long-term survival of dopaminergic neurons^12,13.

Oxidative stress

Loss of dopamine in Parkinson’s disease causes oxidative stress. Dopamine is normally metabolized by monoamine oxidase (MAO)-B, leading to the generation of hydrogen peroxide. Glutathione normally clears excess hydrogen peroxide from the cell, with failure to do so leading to the production of reactive oxygen species (ROS) capable of initiating a cytotoxic cascade of lipid peroxidation and cell death. Reduced levels of glutathione in Parkinson’s brains¹⁴, coupled with a high dopamine turnover (a compensatory mechanism for reduced dopaminergic neurons), lead to high levels of peroxidation and cellular damage.

Dopamine-quinone is another product of spontaneous and enzymatic dopamine oxidation. Dopamine-quinone is capable of causing mitochondrial dysfunction or modifying proteins, such as alpha-synuclein, parkin, DJ-1, and UCH-L1, dysfunction of which can lead to Parkinson’s disease pathophysiology^15,16.

Mitochondrial dysfunction

Excessive mitochondrial damage contributes to Parkinson’s pathogenesis. Damage to mitochondria, either as a result of reduced activity of complex I in the electron transport chain, lipid membrane peroxidation by ROS, or genetic-induced alterations, can lead to the release of cytochrome c, triggering apoptosis^15,16. Parkin and PINK1, for example, localize to mitochondria and are associated with normal function¹⁷. PINK1 accumulates on the outer membrane of damaged mitochondria where it recruits parkin to the dysfunctional mitochondria, triggering mitophagy¹⁸. Accumulation of dysfunctional mitochondria can lead to early-onset Parkinson’s¹⁸.

Neuroinflammation

Dopaminergic neurons intrinsically generate high levels of ROS, making them susceptible to this chain of oxidative stress events. The progressive loss of dopaminergic neurons is associated with chronic neuroinflammation through the activation of microglia by proteins such as alpha-synuclein, parkin, LRRK2, and DJ-1^19,20. Overactive or chronically activated microglia can release ROS²¹ and cause an uncontrolled inflammatory response, producing a self-perpetuating cycle of neurodegeneration²².

LRRK, in particular, is thought to be a key modulator of neuroinflammation²³. LRRK is highly induced in response to alpha-synuclein overexpression, while LRRK2 knockout rats are resistant to neuroinflammatory responses and dopaminergic neurodegeneration following alpha-synuclein overexpression²⁴.

FirePlex seminar with MJFF

Join presenters Dr Nicole Polinski from The Michael J. Fox Foundation (MJFF) for Parkinson's research and Dr Elnaz Atabakhsh from Abcam to learn more about how the FirePlex^® multiplex platform is helping to profile neuroinflammatory biomarkers in patient samples.​

The webinar covers

• Introduction to Parkinson's disease and The Michael J. Fox Foundation (8 minutes)
• Importance of investigating inflammation in Parkinson's disease (8 minutes)
• Future directions of Parkinson's disease research (30 minutes)
• The FirePlex technology platform and biomarker profiling (10 minutes)

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Rabbit monoclonal antibodies for Parkinson’s disease research

In collaboration with MJFF, we developed antibodies for Parkinson’s research. These are part of a larger catalog of research tools available through MJFF.

LRRK2 

LRRK2 gene mutations are the most common cause of inherited Parkinson's disease. While it is the focus of intensive research in the Parkinson's field, a lack of high-quality LRRK2 antibodies has been a major roadblock to the successful development of LRRK2-based therapies.

After primary characterization organized by MJFF and feedback from the Parkinson’s disease research community, three rabbit monoclonal clones exhibiting the best performance were selected for distribution via Abcam.

"LRRK2 antibodies are critical to help move Parkinson's research forward. The three unique clones chosen for initial release were identified based on several months of testing by our large network of Parkinson’s researchers... we are excited that they [Abcam] will continue to help MJFF remove barriers to developing Parkinson's therapies."

- Dr Mark Frasier, Vice President of Research Programs at MJFF

• See a complete list of LRRK2 antibodies and their characterization data.

Alpha-synuclein 

SNCA was the first gene to be linked to Parkinson’s disease and remains the most promising link to Parkinson's pathogenesis. Alpha-synuclein, the protein encoded by this gene, is a major component of Lewy bodies, a type of intraneuronal aggregate. Build up of these aggregates within neurons causes the loss of motor control associated with Parkinson's disease. 

DJ-1

DJ-1 (PARK7) is thought to act as a sensor of oxidative stress in cells. It has increasingly been investigated for modifications that occur as a result of disease pathogenesis, including protein oxidation. DJ-1 is responsible for the activation of microglia leading to neuroinflammation associated with Parkinson's disease. 

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RAB GTPases

Certain Rab GTPases (Rabs) are linked to Parkinson’s disease through disease-associated mutations or interactions with key Parkinson’s disease-related proteins like alpha-synuclein and LRRK2. Given this relationship to Parkinson’s disease and the known role of Rabs in endocytic trafficking, these proteins are important targets for understanding Parkinson’s disease pathobiology and target engagement.

RAB ELISA kits

References

1. Obeso, J. a, Rodriguez-Oroz, M. C., Stamelou, M., Bhatia, K. P. & Burn, D. J. The expanding universe of disorders of the basal ganglia. Lancet 384, 523–31 (2014).

2. Guo, J. L. & Lee, V. M. Y. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat. Med. 20, 130–138 (2014).

3. Cheng, H. C., Ulane, C. & Burke, R. Clinical progression in Parkinson’s disease and the neurobiology of Axons. Ann. Neurol. 67, 715–725 (2010).

4. Osterberg, V. R. et al. Progressive aggregation of alpha-synuclein and selective degeneration of lewy inclusion-bearing neurons in a mouse model of parkinsonism. Cell Rep. 10, 1252–60 (2015).

5. Thomas, B. & Beal, M. F. Parkinson’s disease. Hum. Mol. Genet. 16, R183–R194 (2007).

6. Bekris, L. M., Mata, I. F. & Zabetian, C. P. The Genetics of Parkinson Disease. 18, 1199–1216 (2013).

7. Klein, C. & Westenberger, A. Genetics of Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2, a008888 (2012).

8. Irwin, D. J., Lee, V. M.-Y. & Trojanowski, J. Q. Parkinson’s disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat. Rev. Neurosci. 14, 626–36 (2013).

9. Lynch-Day, M. A., Mao, K., Wang, K., Zhao, M. & Klionsky, D. J. The Role of Autophagy in Parkinson’s Disease. Cold Spring Harb. Perspect. Med. 2, a009357–a009357 (2012).

10. Ciechanover, A. & Kwon, Y. T. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp. Mol. Med. 47, e147 (2015).

11. Xilouri, M., Brekk, O. R. & Stefanis, L. Alpha-synuclein and Protein Degradation Systems: a Reciprocal Relationship. Mol. Neurobiol. 6, 1–15 (2012).

12. Laguna, A. et al. Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson’s disease. Nat. Neurosci. 18, 826–835 (2015).

13. Isacson, O. Lysosomes to combat Parkinson’s disease. Nat. Neurosci. 18, 792–793 (2015).

14. Martin, H. L. & Teismann, P. Glutathione--a review on its role and significance in Parkinson’s disease. FASEB J. 23, 3263–3272 (2009).

15. Hwang, O. Role of oxidative stress in Parkinson’s disease. Exp. Neurobiol. 22, 11–7 (2013).

16. Blesa, J., Trigo-Damas, I., Quiroga-Varela, A. & Jackson-Lewis, V. R. Oxidative stress and Parkinson’s disease. Front. Neuroanat. 9, 1–9 (2015).

17. Scarffe, L. a., Stevens, D. a., Dawson, V. L. & Dawson, T. M. Parkin and PINK1: Much more than mitophagy. Trends Neurosci. 37, 315–324 (2014).

18. Pickrell, A. M. & Youle, R. J. The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease. Neuron 85, 257–273 (2015).

19. Lee, E.-J. et al. α-Synuclein Activates Microglia by Inducing the Expressions of Matrix Metalloproteinases and the Subsequent Activation of Protease-Activated Receptor-1. J. Immunol. 185, 615–623 (2010).

20. Wilhelmus, M. M. M., Nijland, P. G., Drukarch, B., De Vries, H. E. & Van Horssen, J. Involvement and interplay of Parkin, PINK1, and DJ1 in neurodegenerative and neuroinflammatory disorders. Free Radic. Biol. Med. 53, 983–992 (2012).

21. Block, M. L., Zecca, L. & Hong, J.-S. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57–69 (2007).

22. Qian, L., Flood, P. M. & Hong, J. S. Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J. Neural Transm. 117, 971–979 (2010).

23. Puccini, J. M. et al. Leucine-rich repeat kinase 2 modulates neuroinflammation and neurotoxicity in models of human immunodeficiency virus 1-associated neurocognitive disorders. J. Neurosci. 35, 5271–83 (2015).

24. Daher, J. P. L., Volpicelli-Daley, L. A., Blackburn, J. P., Moehle, M. S. & West, A. B. Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc. Natl. Acad. Sci. U. S. A. 111, 9289–94 (2014).