# Progress and Prospects in Parkinson's Research/Magazine Section/Getting the ball rolling

This Magazine Section could be a focal point of this Wikiversity learning project. But right now, as we prepare to announce the project to all and sundry, it is virtually empty!
What are the most exciting recent developments in Parkinson's research? Who can write about them here? How do they all fit within the bigger picture?
Here are a few ideas to get the ball rolling. As this is a Wikiversity learning project, the invitation to add other topics is open to everyone.

## The Top Topics

Around a dozen dominant themes can be discerned at this time from amongst the scores of papers on Parkinson's research published every month. Here are just eight: Genetics, Re-positioning of Existing Drugs, Anti-inflammatories, Risk factors, Biomarkers and diagnosis, Alpha-synuclein, induced pluripotent stem cells (iPSCs) and Neuroprotection/neurorestoration. These topics, of course, overlap considerably.
Let's start describing and discussing some of these and comment on their significance and how they fit into the whole Parkinson's research scene. Please feel invited to add your own contributions in the same vein.

### Biomarkers for the early diagnosis of Parkinson's

There has recently been a lot of activity in the scientific literature in this area. Interest is surely based on the idea that, if and when a therapy is discovered that will slow down the progression of the disease, the greatest benefits will be achieved the earlier the treatment is given - and could be particularly beneficial if given before the motor symptoms emerge. Practicalities aside about why one would choose to be screened for Parkinson's if no symptoms of that disease had yet arisen, there are now a range of different biomarkers that, taken together, could give a pretty good indication that a person was in the prodromal stage.

#### Voice and Smell

Work analysing voice patterns of people with Parkinson's using new sophisticated algorithms has resulted in a recent 'crowd-sourcing' project. The Parkinson's Voice Inititative is a practical application of the research done by Dr Max Little at Oxford University for his PhD degree and aims to collect sufficient voice information needed "to build a system to screen for and monitor the symptoms of this debilitating disease."
A summary of the project's aims says: "This project aims to collect 10,000 sustained phonations ('aaah' vocal sounds) through telephone-quality digital audio lines, under realistic, non-lab conditions, to test the hypothesis that it is possible to detect Parkinson's disease through these recordings. ... " Work so far has enabled them to claim that the technique goes beyond mere detection of Parkinson's: "Furthermore, we are able to accurately predict the severity of Parkinson's symptoms on a standard clinical scale (UPDRS)." This is an exciting development because widespread use of this technique would be very cheap since the voice recording takes only 30 seconds, can be taken over the telephone and the computer analysis can be done almost instantaneously. Data collection has now finished but a follow-up project is planned. Intending participants are asked to complete a short on-line questionnaire
Loss of the sense of smell has for a long time been associated with the development of Parkinson's. Not all people with Parkinson's lose their sense of smell but somewhere around one in ten of people with hyposmia as it is called go on to develop Parkinson's in later years. So if there is a serious requirement to pick out those in the population who are at risk of developing Parkinson's, maybe the approach taken by Dr U Liebetrau in Cologne for public smelling tests, as reported in Medical News Today, is worth considering.

#### Quality of life symptoms

A recent study has explored non-motor symptoms that precede diagnosis and has documented declines in physical and mental health, pain, and emotional health beginning several years before the onset of the disease and continuing thereafter. Details can be found in a press release for the article that appeared in the Journal of Parkinson's Disease.

#### Alpha-synuclein in the colon

Two papers this year from the Rush Medical College in Chicago report research into the occurrence of aggregated alpha-synuclein in the colon. The first, perhaps unsurprisingly, since there has been a lot of evidence over recent years that alpha-synuclein pathology occurs in the enteric nervous system early on in Parkinson's, reports the detection of such pathology in gut samples from actual Parkinson's patients whereas the second reports that samples taken during colonoscopies and sigmoidoscopies undertaken for other purposes on people who only later were diagnosed with Parkinson's also revealed alpha-synuclein pathology. In both cases other patients who did not have Parkinson's (but in some cases had inflammatory bowel disease) did not display the Parkinsonian pattern. If further work confirms the occurrence of aggregated alpha-synuclein in the sub-mucosa of the colon as a reliable biomarker for Parkinson's even before clinical signs appear, screening through colonic biopsies, especially as part of routine sigmoidoscopies, would become feasible. It would be a particularly valuable diagnostic technique in cases where the risk factors for Parkinson's were already quite high (for instance where there was a family history of Parkinson's or where symptoms like constipation, hyposmia, REM Behaviour Disorder or any of the other biomarkers discussed here were already present).

#### A blood test for a gene-expression signature

The pathological process going on in a person with Parkinson's causes a change in gene expression i.e. it changes what genes are turned on and by how much. We are not talking here about the genetic mutations or variations which are associated with Parkinson's but how some ordinary genes raise or lower their output of proteins and other substances in reaction to the pathogenic situation. An international team has recently published their results on identifying a profile or signature of the expression of just 5 genes which they believe could give a reliable indication of Parkinson's even before clinical symptoms have emerged. Fortunately the altered gene expression can be detected in blood samples and not just in nervous system fluids such as the cerebrospinal fluid which means that a blood test could eventually be developed for reliably diagnosing Parkinson's at a very early stage. At the moment it is well known that misdiagnosis is quite common in the early stages. Further work is needed, however, on how well the expression signature differentiates Parkinson's from other neurological conditions such as MSA and PSP. Further work is also needed to study how the levels of gene expression vary over the course of the disease in order to see whether measurements could also give a reliable indication of the stage of disease progression.

#### An antibody as a biomarker

A recent paper reports on an antibody which can flag the presence of an aberrant form of alpha-synuclein. They say "This new antibody will enable us to find the pathological conformation in bodily fluids such as blood or CSF" which indicates that they are positioning this development primarily as a valuable biomarker for the disease.

#### More on Biomarkers for Parkinson's

For more on Biomarkers and Biomeasures see Biomarkers for PD and Measurement of Parkinson's Disease Progression.

### Alpha-synuclein

Alpha-synuclein is central to the current understanding of Parkinson's pathogenesis (and the pathogenesis of other neurodegenerative diseases) and is prompting so many ideas for confronting the disease. Recent work has been looking at how to stop this protein aggregating, to remove it as aggregation starts or to unpick the aggregates once they have formed. Other notable work has begun to discover more about how it moves from cell to cell. Yet other recent research has focused on the vital issue regarding which forms of it are the toxic ones and the mechanism for their formation. Let's look at the last first.

#### Toxic oligomers

A recent paper describes the results of some international, muliticentre work that has probed the way that molecules of alpha-synuclein associate together to form oligomeric structures and go on to form fibrils and higher-order aggregates that eventually form Lewy bodies and Lewy neurites in neurons in Parkinson's patients. The researchers were able to discriminate between different types of oligomer. They found that the oligomers (type A) that were initially formed from the monomeric Alpha-synuclein were very much less cytotoxic than the oligomers (type B) to which they were converted. The cytotoxicity was due to the stimulation of production of reactive oxygen species (ROS). They demonstrated that the pathway from monomer through type A and type B oligomers to higher order filaments and aggregates was a two-way process. It is noteworthy that they say "The structural conversion is remarkably slow, ... suggesting that there is a significant period of time for the cellular protective machinery to operate and potentially for therapeutic intervention, prior to the onset of cellular damage." The implication here is that in cases of Parkinson's the cellular protective machinery fails to clear up the type A oligomers before they convert to the more damaging oligomers which, they discovered, are more resistant to degradation. They suggest that maybe there is the opportunity to provide some therapeutic help here.

#### A vaccine for alpha-synuclein?

An Austrian company is about to start a Phase I trial of a compound which it has named PD01A which they hope will prove to be the first vaccine for Parkinson's. Despite the scant details, it would appear that there is persuasive evidence that PD01A could be effective because the Michael J Fox Foundation is financially supporting the trial. Yet the mode of action of PD01A as described appears simply to be to attack and remove native alpha-synuclein. On the surface this approach would appear questionable as only in a minority of cases is the disease thought to result from the overexpression of the protein.
The recent paper, also from Vienna, referred to in the section above (An_antibody as a biomarker) reports on an antibody which can flag the presence of an aberrant form of alpha-synuclein. But the abstract makes no mention of any future application of the antibody as part of a pharmacological approach to actually remove the damaging form of the protein in order to halt disease progression.

#### A drug to clear aggregated alpha-synuclein

A drug called latrepirdine is entering Phase II of its clinical trials. This follows preclinical studies in mice which suggested the compound cleared misfolded protein aggregates of various kinds by boosting autophagy (which is one part of the body's garbage collection mechanism). Latrepirdine has already been used as an antihistamine and so, if it proved effective, should be able to be brought to the clinic in a shorter time than for a brand new drug. Yet the authors see it rather as " a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease ...". I.e. it would be a useful prototype for designing more effective drugs which work in a similar way. Earlier work suggested that latrepirdine was itself not that effective.
Work like this is an example of the activity going on to find effective neuroprotective therapies.

#### How Parkinson's spreads through the nervous system

Since the evidence provided ten years ago by Prof Heiko Braak that alpha-synuclein pathology spreads in a stage-wise manner through the brain, there has been a lot of conjecture about the mechanism of the transmission. The latest open access paper on this by Patrick Brundin et al describes cell-to-cell transfer of pathogenic alpha-synuclein from host cells to neural grafts in rats. The results support the hypothesis that Parkinson's pathology is spread by altered alpha-synuclein passing into the extracellular space from the axons of neurons and then being actively transported into recipient neurons by endocytosis. They also observed the transported alpha-synuclein acting as a 'seed', attracting endogenous alpha-synuclien produced by the rat neuron and presumably starting to convert it to the pathogenic form. In conclusion they say "Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology."

#### More on the pathogenic role of alpha-synuclein

will be be found under The Current Parkinson's Paradigm

### Induced Pluripotent Stem Cells

The excitement over stem cells over recent years has been because, for Parkinson's, the hope was held out that it might be possible through transplantation to replace lost dopaminergic neurons. The success in being able to induce some of a patient's own non-neural cells to become dopaminergic neurons certainly in the long run supports the hope that a cell-replacement therapy can be developed. But some early successes of work in the induced Pluripotent Stem Cell (iPSC) field has shifted the focus to exploiting the ability to examine human cells affected by Parkinson's and to developing test beds for potential new therapies. Three recent papers illustrate the important progress that can be made in this respect.
All three investigations generated iPSCs from patients with familial forms of Parkinson's but one of them, by a Spanish team, also used cells from idiopathic Parkinson's patients (i.e. where the patients do not have the common genetic variations associated with the disease). It is well worth reading the Discussion section of this paper, which is Open Access, because it describes how Parkinson's pathogenic changes were present in the cells from both idopathic and familial patients while they were absent in the control cells. They also found that the dysfunction related to the autophagy system (which is part of the cell's garbage collection mechanism). Interestingly they say "intrinsic cell-autonomous factors, rather than environmental influences, appear to be sufficient to trigger neurodegeneration of [dopaminergic neurons] from PD patients". In other words the risk of idiopathic Parkinson's is an in-built vulnerability which needs minimal environmental triggering; they surmise that the stress of the experimental in vitro setup was sufficient to trigger the observed pathogenic process.
In the other paper that was also open access, the California team dwelt on the utility and potential of iPSC work whereas the third paper by a multicentre team in the USA made some progress in protecting the cells from the neurodegeneration resulting from the oxidative stress observed by the administration of a range of agents. This is described in more detail here

#### More on iPSCs

will (eventually) be found at Modelling PD/iPSC

### Other Topics

Interesting work continues to be done in areas such as neuroprotection/neurorestoration, the better treatment of Parkinson's symptoms and the repositioning of existing drugs. Please feel invited to write sections on these.