Article: "Potential Cause of Parkinson's Disease Points to New Therapeutic Strategy"


Our media article focuses on a potential new treatment for Parkinson's disease inspired by recent research findings. Published on 24/07/13 on, the article is based on a news release from The Scripps Research Institute (TSRI). It effectively summarises a study published in the leading scientific journal Molecular and Cellular Biology by scientists from TSRI (Ekholm-Reed et al, 2013). The media item highlights Ekholm-Reed’s persistent research despite lack of funding, which has finally unveiled the link between the loss or mutation of the parkin gene and the death of neurons under oxidative stress. This ground-breaking finding is significant, leading to renewed hopes for a better treatment for Parkinson’s disease. It of particular importance as the findings may also be able to be applied to treatment of other neurological diseases.

Parkinson’s disease is a debilitating disorder that renders sufferers incapable of controlling their own movements. It affects approximately 1 in every 350 people, predominately those aged over 60, with 30 new cases each day in Australia alone (Deloitte Access Economics, 2011). Further, these statistics have been increasing considerably over the last decade with Australia's aging population. Sadly, as there is no known cure, sufferers are only offered treatments that relieve their symptoms.The incomplete understanding of the causes of Parkinson's disease and its high prevalence contributed to the choice of this topic and article. Evidently, further research is needed in this field to prevent and treat the intense and incapacitating symptomology.


2.1. Pathology and symptoms

Parkinson’s disease is a neurological degenerative disorder. The hallmark pathology of is progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain which project to the striatum (Lew, 2007; Davie, 2008; Dauer & Prezedborski, 2003). In a majority of cases, Parkinson’s disease is also associated with presence of Lewy bodies, abnormal protein aggregations found inside neuronal brain cells (Lew, 2007; Davie, 2008). As the dopaminergic neurons in the substantia nigra are primarily responsible for smooth control of voluntary muscle movement, the primary symptomology of the disorder is manifest as incapacitating motor deficits (Hwang, 2013). The three clinically diagnostic symptoms are tremor, bradykinesia (slowed movement), and muscular rigidity (Parkinson’s Australia, 2013; Shulman et al., 2011). These significant impairments in balance and co-ordination are coupled with cognitive disturbances, most notably dementia and depression in the later stages (Jankovic, 2008). See Diagram 1.

Diagram 1: Pathology and Symptoms (Parkinson's Disease Foundation)

2.2. Causal factors

The aetiology of Parkinson's disorder remains unknown, with most cases considered idiopathic in origin (Hwang, 2013). Environmental factors such as exposure to pesticides, organic solvents, plant-derived toxins and bacterial and viral infection are implicated in the disorder (Greenamyre & Hastings, 2004). Further, genetics play a role, with rare familial forms of the disorder constituting a small proportion of cases (Lew, 2007). Additionally, normal age-related neuronal decline is a contributing factor (Lew, 2007). Despite the macro-level causal discrepancies, oxidative stress appears to be the immediate precursor to neuron dysfunction and atrophy (Hwang, 2013).

2.3. Oxidative stress

Oxidative stress is an imbalance of reactive oxygen species and the antioxidants responsible for detoxifying them. Dopaminergic neurons are particularly vulnerable to increased levels of reactive oxygen species such that cell death can occur with even mild, sustained oxidative stress. Mitochondrial dysfunction, neuroinflammatory responses and dopamine metabolism are all causes of oxidative stress which may affect the neurons of the substantia nigra (Hwang, 2013). That oxidative stress can result from a wide variety of both intracellular dysfunctions and external influences, supports the theory of interaction between environmental, genetic and age-related factors as causing Parkinson’s disease.

2.4. Risk genes

To date, several rare single gene mutations have been identified as causal or risk factors for Parkinson’s disease (Davie, 2008). Some of these key genes are those encoding the nuclear proteins parkin, α-synuclein, UCHL-1, DJ-1 and PINK1 (Greenamyre & Hastings, 2004). Despite their distinct cellular roles, the proteins are linked mechanistically by their contributions to protein regulation and mitochondrial function (see Diagram 2). Altered expression of these genes can lead to oxidative stress and hence the cellular pathology characteristic of Parkinson’s disorder (Greenamyre & Hastings, 2004).

risk genes.PNG
Diagram 2: Greenamyre & Hastings, 2004

2.5. Parkin cascade

2.5.1. Mechanism
Of the genes identified as linked to Parkinsonism, mutations of the recessive autosomal PARK2 gene which codes parkin is one of the most common causes of inherited Parkinson’s disease (Kahle & Haass, 2004). Parkin is a specific ubiquitin ligase enzyme which regulates concentrations of cellular proteins. Addition of ubiquitin (a small regulatory protein) to a substrate protein by parkin marks that substrate for proteasomal degradation. Normally, this tagging process, known as ubiquitination, prevents accumulation of harmful substrates. When parkin is dysfunctional, the removal of toxic aggregates from cells is hindered (Kahle & Haass, 2004).

Despite identification of numerous substrates for parkin, early research was unable to conclusively demonstrate the exact mechanisms by which parkin inactivity led to the pathogenesis associated with Parkinson’s disease (Ekholm-Reed, Goldberg, Schlossmacher & Reed, 2013). More recently, Ekholm-Reed et al. have identified parkin’s involvement in regulating levels of another ubiquitin ligase, Fbw7β, whose downstream actions are important for normal cellular functioning.

Fbw7β modifies levels of the induced myeloid leukemia cell differentiation protein (Mcl-1) through its action as an ubiquitin ligase (Ekholm-Reed, Goldberg, Schlossmacher & Reed, 2013). Mcl-1 regulates the rate of cellular apoptosis (programmed cell death) through selective transcription in response to neuronal needs. Normally, the low levels of Fbw7β maintained by parkin’s ubiqutination ensure that enough MCl-1 is present in neurons, rendering them resistant to apoptosis. However, when parkin malfunction allows levels of Fbw7β to increase, Fbw7β causes excessive ubiqutination of MCl-1 such that MCl-1 levels drop. Without sufficient MCl-1, sensitivity of brain cells to oxidative stress increases significantly, eventually leading to degeneration of dopaminergic neurons and Parkinsonism (Ekholm-Reed, Goldberg, Schlossmacher & Reed, 2013). See Table 1 for a diagrammatic summary.

Table 1: Downstream effects of parkin mutation (c)
Normal functioning
Mutation of PARK2 gene
Normal levels of parkin
Parkin tags excess Fbw7β for degradation
Normal levels of Fbw7β
Fbw7β tags excess Mcl-1
Normal levels of Mcl-1
Cells resistant to apoptosis,withstand oxidative stress
Malfunctioning parkin/low levels of parkin
Parkin unable to tag Fbw7β for degradation
High/increased levels of Fbw7β
Too much tagging of Mcl-1 for degradation
Low/decreased levels of Mcl-1
Cells prone to apoptosis,sensitive to oxidative stress

2.5.2. Implications for a potential new treatment
As a result of this research, Ekholm-Reed et al. suggest that a new approach to treat Parkinson’s disease should involve developing a mechanism to inhibit Fbw7β, thus causing an increase in MCl-1 levels which should in turn enhance neuronal resistance to oxidative stress. This 'neuroprotective' strategy would be highly beneficial as it would focus on early prevention, rather than symptom management. Additionally, minimising the vulnerability of neurons to oxidative stress may also help prevent other neurodegenerative conditions. However, further research is required before development of such a treatment can begin.

2.6. Existing treatments

2.6.1. Pharmacological therapies
As death of dopaminergic neurons is thought to cause the symptoms of Parkinson’s disorder, pharmacological therapies aim to increase levels of dopamine and activity of dopaminergic neurons in the brain. However, direct administration of dopamine is ineffective as it is quickly metabolised in the periphery, producing undesirable side effects (Chen & Pahwa, 2008). Dopamine is also unable to cross the blood-brain barrier to reach the striatum or substantia nigra. See Table 2 for a summary of pharmacological treatment options.

pharm therapies.PNG
Table 2: Pharmacological therapies (National Collaborating Centre for Chronic Conditions, 2006)

2.6.2. Levodopa
Levodopa (L-DOPA) is the exogenous precursor to dopamine and other catecholamines. In the body, L-DOPA molecules undergo decarboxylation via a multi-enzymatic cascade to become dopamine. L-DOPA is often administered orally where it eventually crosses the blood-brain barrier. It is decarboxylated into dopamine at presynaptic terminals of dopaminergic neurons in the striatum, then metabolised by monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT) (Goldenberg, 2008). To prevent premature decarboxylation by digestive enzymes in the periphery, L-DOPA is often administered alongside decarboxylase inhibitors, especially carbidopa (Goldenberg, 2008).

In early stages of therapy, L-DOPA significantly reduces tremor, rigidity and bradykinesia. However, the effect weakens in long-term treatment (Goldenberg, 2008). Increasing the dosage or frequency of L-DOPA will alleviate symptoms; however, exceedingly high dosages cause dyskinesia. In later stages of treatment, patients will often experience “off” periods where L-DOPA produces no therapeutic effect and “on” periods where they will experience dyskinesia (Nelson, 1990).

2.6.3. Dopamine agonists
As an alternative to increasing dopamine directly, Parkinson’s disease symptoms can also be reduced through administration of dopamine agonists. Dopamine agonists mimic the effects of dopamine by binding and activating dopamine receptors. They have the advantage of being more selective than L-DOPA, and typically used alongside L-DOPA and carbidopa to provide stronger benefits. Dopamine metabolism itself contributes to production of free radicals which consequently adds to oxidative stress responsible for neuronal death. The use of dopamine agonists which does not require metabolism minimises the extent of this stress (Schapira, 2004). However, dopamine agonists are less effective than L-DOPA and may increase the intensity of side effects, particularly dyskinesia, hallucinations and nausea (Goldenberg, 2008).
L-DOPA diagram.png
Diagram 3: Mechanism of L-DOPA treatment (c)

2.6.4. Dopamine metabolism inhibitors
Reducing the metabolism of L-DOPA or dopamine in the brain through administration of decarboxylate inhibitors is another approach to treat Parkinson’s disease symptoms. COMT inhibitor drugs prevent the metabolism of L-DOPA within the striatum, leaving higher levels of L-DOPA available to convert to dopamine to control movement. They reduce the ‘wearing off’ effect of L-DOPA, decreasing metabolism within the body. Side effects of this drug include dyskinesia, nausea and diarrhoea (Goldenberg, 2008).

MAO is another dopamine-metabolic enzyme commonly targeted by drug treatment. It has two subtypes: MAO-A and MAO-B, the latter predominantly responsible for dopamine metabolism. Earlier MAO inhibitors were non-selective and produced unwanted metabolites. Modern selective MAO inhibitors such as Selegiline and Rasagiline have been developed for clinical use in early Parkinson's disease. MAO inhibitors may additionally provide some anti-apoptotic effect (Ravina et al, 2003).

2.6.5. Deep Brain Stimulation
A notable surgical treatment is deep brain stimulation (DBS). DBS involves bilaterally inserting pacemakers into the brain, especially in the globus pallidus or the subthalamic nucleus. The pacemaker delivers constant electrical stimulation to the target location, altering neuronal activity. Specifically controlled DBS can prevent symptoms of Parkinson’s disease either directly by reducing akinesia and rigidity or indirectly by targeting L-DOPA induced dyskinesia. (Benabid, 2003). The mechanism for these therapeutic effects is still being debated; a possible explanation is that it disrupts the abnormal neural messages characteristic of Parkinson’s disease (Benabid, 2003).

DBS is often used in later stages of Parkinson's disease after L-DOPA treatment begins to lose effectiveness. DBS should be implemented before this point so that the patient is able to retain some control over their condition (Benabid, 2003). Due to dyskinesia being a side effect of L-DOPA treatment, L-DOPA dosage is decreased in order to increase effectiveness of DBS (Benabid, 2003).


3.1. Background is an internet website that offers readers free access to the latest scientific discoveries from the world’s leading universities and research organisations. It covers all fields applied science, enabling the general public to access a broad spectrum of science topics. Articles shown on the site are selected from press releases based on relevant journal articles that are submitted to which are edited for high quality and relevance.

3.2. Target Audience

The article was originally published in the 2013 Press Release of The Scripps Research Institute. However, we accessed it via Therefore, we can assume that the article's target audience has some scientific background. The article is located under the ‘Mind and Brain | Parkinson’s’ section, suggesting that the intended audience has a psychological/neurological background. It contains scientific jargon making it potentially challenging for unfamiliar readers; however, the authors explain these complex contextual concepts such that readers can follow. As the article discusses one of the most well-known major disorders, learning about a treatment would be able to engage many readers.

3.3. Biases and validity

The media article presents a somewhat biased perspective. On one hand, it avoids glorifying the potential new treatment as the most effective. Instead, it highlights the broad nature of the strategy, implying that the area of study requires further research for better results. However, the extent of knowledge about the potential treatment is somewhat exaggerated. This is demonstrated through the title which suggests that a clinical and therapeutic treatment has been developed already. Further, the applicability of the treatment is sensationalised. Genetic causes for Parkinson's disease only represent ‘between 5 and 15% of cases’, and a smaller percentage again are due to mutations on the parkin gene. Another article similarly suggests that only ‘10% of Parkinson’s disease cases is caused by gene mutation, one being parkin’ (LMU, 2013). This emphasises that the neuro-protective therapeutic strategy may in fact only be effective in less than 10% of patients. Again, more bias is shown considering that it only represents the opinions of researchers associated with the study. The quality of information in the article is fairly valid, however the validity can be improved by incorporating the opinions of other neurologists. In saying this, the authors effectively summarise and simplify the findings of Ekholm-Reed et al.'s journal article, but compromises the media article's validity by using misleading language and failing to acknowledge the views of other neurologists.

3.4. Evaluation

The purpose of this article is to inform the public of the potential in targeting a mechanism which inhibits Fbw7β to increase neuronal resistance to oxidative stress, a technique which may assist cases of Parkinson's disease caused by parkin mutation. The media article succinctly explains the potential causes of Parkinson’s disease from the effects parkin and how this information has allowed conceptualisation of a new therapeutic strategy. The article also contains statements from the senior authors of the journal article, helping readers understand and consolidate the information. As a result, the article is both engaging and informative. However, it could be improved by providing a opinions of researchers in the wider field, and by more accurately describing the applicability and efficacy of the potential strategy to current cases of Parkinson's disease.


4.1. Search strategy

To decide upon a topic of choice, we brainstormed ideas of concepts we each had in mind. We all wanted to research a neurological disorder that is not well understood. We conducted a quick Google search on all our ideas and ultimately settled on Parkinson's Disease. To find our media item, we broadly searched news items on treatments for Parkinson's disease with a focus on articles published within the last year. After independent research we created a short-list of possible media items, and after the group read this list, we unanimously selected our final article.

As our chosen media item was a summary of a scientific journal article, our first approach was to source this original article through the UNSW library website. We primarily used UNSW library website and Google Scholar to find relevant peer-reviewed articles which explained the aetiology of Parkinson's disorder and presented hypotheses for its causal mechanisms. This focus on broader contextual primary literature was crucial to our understanding of the key ideas which were assumed knowledge in the scientific article. To find more general background information on symptoms and prevalence, we utilised information from government publications, the Australian Bureau of Statistics and Parkinson's Australia. As our media article was based on a news release from the Scripps Research Institute, we used their website to source contextual information to assist us with analysis of its validity.

4.2. Discussion of peer review comments

Comments provided by our peer assessors presented us with a much needed objective view of our wikipage. Whilst the overall comments were positive, they also identified obvious flaws such as grammatical errors and poor choice of words. These elementary issues were easily solved and altered accordingly. Similarly, any structural and formatting issues were quickly fixed as suggested.

As noted by our peers, the introduction had issues with structure and content validity. As suggested, a more thorough justification for choice of topic was added with suitable statistics. We agreed with our peers that the introduction was content laden, thus the introduction of Parkinson's Disease was shifted into the neuroscientific context. A reviewer suggested a more in depth summary of the article in the introduction, unfortunately we disagreed with this suggestion as it would fill the introduction with unexplained jargon.

In the neuroscientific context section, we incorporated more background information on the existing treatments and added more diagrams to support the written information as suggested by many of our reviewers. We agreed that both these changes were essential improvements. One reviewer suggested that the neuroscientific context was too focused on oxidative stress. However, we believe that an understanding of oxidative stress is the central focus of our article and the treatment approach it proposes. In response to the comment, we instead sought to improve clarity and logical flow within this section to highlight the relevance of oxidative stress and to the article. Another reviewer suggested incorporating more information on the benefits and drawbacks of the potential new treatment approach, however we were unable to do this as no such perspectives are yet available given the recency of the article.

One comment pertaining to the analysis section, suggested that we clearly delineate between referring to our media item and the original journal article. This was easily remedied as per the reviewers suggestion. We also enhanced our analysis by adding a more thorough discussion on biases and validity to improve upon the sound foundation established in our draft.

Overall, we found the reviewer comments to be both detailed and informative as they indicated many areas for improvement. We felt confident in accepting some thoughtful feedback, and were able to use the comments to improve our whole page. Additionally, the opportunity to review others' pages gave us further ideas of how to improve our own.


Benabid, AL 2003, 'Deep brain stimulation for Parkinson’s disease,' Current Opinion in Neurobiology, vol.13 pp, 696–706.

Chen, JC & Pahwa, R, 2008, ‘Pharmacologic Management of Parkinson’s Disease: Choice of Initial Therapy in Early Disease,’ Journal of Pharmacy Practice, vol. 21, pp.244-253.

Dauer, W & Prezedborski, S, 2003, 'Parkinson’s Disease: Mechanisms and Models', Neuron, 39, 889-909.

Davie, CA 2008, ‘A review of Parkinson’s disease’, British Medical Bulletin, vol. 86, pp. 109-27.

Deloitte Access Economics, 2011 'Living with Parkinson's Disease - update' Parkinson's Australia, October, viewed 10 September 2013,

Doshi, PK 2011, ‘Long-term Surgical and Hardware-Related Complications of Deep Brain Stimulation,’ Stereotactic and functional neurosurgery, vol. 89, pp.89-95.

Ekholm-Reed, S, Goldberg, MS, Schlossmacher, MG & Reed, SI, 2013, ‘Parkin-dependent degradation of the F-box protein Fbw7β promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1’, Molecular and Cellular Biology, vol. 33, no. 18, pp. 3627-43.

Goldenberg, MM 2008, ‘Medical Management of Parkinson’s Disease,’ P&T, vol. 33.

Greenamyre, JT & Hastings, TG 2004, ‘Parkinson’s – divergent causes, convergent mechanisms’, Science, vol. 304, pp.1120-2.

Hwang, O 2013, ‘Role of oxidative stress in Parkinson’s disease’, Experimental Neurobiology, vol. 22, no. 1, pp. 11-7.

Jankovic, J 2008, 'Parkinson's disease: clinical features and diagnosis', Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 4, pp. 368-76.

Kahle, PJ & Haass, C 2004, ‘How does parkin ligate ubiquitin to Parkinson’s disease?’ European Molecular Biology Organization Reports, vol. 5, no. 7, pp. 681- 5.

Lew, M 2007, ‘Overview of Parkinson’s disease’, Pharmacotherapy, vol. 27, no. 12, pp.155S-60S.

Ludwig-Maximilians-Universitaet Muenchen (LMU) 2013, 'Parkinson's disease: Parkin protects from neuronal cell death', Science Daily, 1 March, viewed 7 September 2013,

National Collaborating Centre for Chronic Conditions 2006, 'Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care.' London: Royal College of Physicians.

Parkinson's Australia, 2013 'Parkinson’s Disease Information Sheet 1.2 Parkinson’s Symptoms' Parkinson's Australia, September, viewed 10 September 2013,

Ravina, BM, Hovinga, CA, Marler, JR, Hart, RG, Fagan, SC & Dawson, TM 2003, ‘Neuroprotective agents for clinical trials in Parkinson’s disease: A systematic assessment.’ Neurology. vol. 60, pp.1234–1240.

Schapira, A 2004, ‘Disease modification in Parkinson’s disease.’ Lancet Neurology, vol. 3, pp.362–368.

The Scripps Research Institute 2013, ‘Potential cause of Parkinson’s disease points to new therapeutic strategy’, ScienceDaily, 24 July, viewed 3 September 2013,

Shulman, JM, DeJager, PL & Feany, MB 2011, 'Parkinson’s disease: genetics and pathogenesis', Annual Review of Pathology: Mechanisms of Disease, vol. 6, pp. 193-222.


Group Members:
Justine Ong (z3418351)
Chris Truong (z3416630)
Natalie Reily (z3414886)
Eric Vi (z3415829)

Topic: Parkinson's Disease
Good topic - plenty of interesting science.
I suggest you try and find out how closely this article matches the media releases from Scripps - is it effectively just recycling their own promotional material?

Division of work initial plan:
Justine - intro, description/ background, appendix
Natalie - neuroscientific context (causes of Parkinson's)
Chris - neuroscientific context (treatment of Parkinson's), analysis
Eric - analysis
Everyone - planning, outlines, research, editing

Division of work final plan:
Justine - introduction
Chris - exiting treatments of PD
Natalie - explanation of neuroscientific context relevant to article
Eric - analysis
Everyone - appendix, search strategy, editing

First complete draft (individual parts) by: September 2nd
First draft + editing submission DUE: September 8th
Review comments from peers by: September 16th
Final draft with with revisions (individual parts) by: September 19th
Final submission due DUE: September 23rd

First meeting was on August 9 - decided on topic