A Selection of Recent News in Parkinson's Disease Research

Today I'll note a selection of recent news from the Parkinson's disease research community. Alzheimer's disease may be where the lion's share of funding goes when it comes to research and development related to neurodegenerative conditions, but work on Parkinson's disease is nonetheless well funded and diverse. This condition is characterized by aggregation of α-synuclein and the death of a small but vital population of dopamine generating neurons. The loss of those neurons results in the loss of motor control observed in patients, but there is a great deal of other damage done to the operation of the brain as a result of abnormal biochemistry downstream of α-synuclein aggregation.

Setting aside the older pharmaceuticals that do little but slow the condition or mask the symptoms, the dominant approaches to development of new therapies involve replacement of the lost dopamine neurons and clearance of α-synuclein. However, there are plenty of other places in which researchers have sought to intervene, in mechanisms that may or may not be downstream of α-synuclein. For example, it was recently demonstrated that cellular senescence in glial cells in the brain contributes meaningfully to the progression of Parkinson's - and thus near future senolytic therapies may produce patient benefits here as in many other age-related conditions. It is also the case that age-related decline in mitochondrial function accelerates the loss of neurons in Parkinson's disease. Where Parkinson's is connected with mutations, such as in the parkin gene, these are mechanisms affecting the maintenance of mitochondria.

Parkinson's disease is similar at the high level to other major neurodegenerative conditions: aggregation of damaging proteins; abnormal inflammatory behavior of the immune system in the brain; faltering mitochondrial function. The lower level details are wildly different, but the theme is the same. To talk about curing any neurodegenerative condition is to talk about curing aging. These conditions are the result of forms of molecular damage and waste buildup that cause aging itself; they can only be effectively dealt with by repairing this damage, and preferably early enough to prevent it from ever reaching pathological levels.

A Proposed Roadmap for Parkinson's Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein

The convergence of human molecular genetics and Lewy pathology of Parkinson's disease (PD) have led to a robust, clinical-stage pipeline of alpha-synuclein (α-syn)-targeted therapies that have the potential to slow or stop the progression of PD and other synucleinopathies. To facilitate the development of these and earlier stage investigational molecules, the Michael J. Fox Foundation for Parkinson's Research convened a group of leaders in the field of PD research from academia and industry, the Alpha-Synuclein Clinical Path Working Group. This group set out to develop recommendations on preclinical and clinical research that can de-risk the development of α-syn targeting therapies.

This consensus white paper provides a translational framework, from the selection of animal models and associated endpoints to decision-driving biomarkers as well as considerations for the design of clinical proof-of-concept studies. It also identifies current gaps in our biomarker toolkit and the status of the discovery and validation of α-syn-associated biomarkers that could help fill these gaps. Further, it highlights the importance of the emerging digital technology to supplement the capture and monitoring of clinical outcomes. Although the development of disease-modifying therapies targeting α-syn face profound challenges, we remain optimistic that meaningful strides will be made soon toward the identification and approval of disease-modifying therapeutics targeting α-syn.

Improved stem cell approach could aid fight against Parkinson's

Scientists have taken a key step towards improving an emerging class of treatments for Parkinson's disease. It addresses limitations in the treatment in which, over time, transplanted tissue can acquire signs of disease from nearby cells. It could aid development of the promising treatment - known as cell replacement therapy - which was first used in a clinical trial this year. Experts hope the approach, which involves transplanting healthy cells into parts of the brain damaged by Parkinson's, could alleviate symptoms such as tremor and balance problems.

Researchers have created stem cells - which have the ability to transform into any cell type - that are resistant to developing Parkinson's. They snipped out sections of DNA from human cells in the lab using advanced technology known as CRISPR. In doing so, they removed a gene linked to the formation of toxic clumps, known as Lewy bodies, which are typical of Parkinson's brain cells. In lab tests, the stem cells were transformed into brain cells that produce dopamine - a key brain chemical that is lost in Parkinson's - in a dish. The cells were then treated with a chemical agent to induce Lewy bodies. Cells that had been gene-edited did not form the toxic clumps, compared with unedited cells, which developed signs of Parkinson's.

"We know that Parkinson's disease spreads from neuron-neuron, invading healthy cells. This could essentially put a shelf life on the potential of cell replacement therapy. Our exciting discovery has the potential to considerably improve these emerging treatments."

Parkinson's disease protein buys time for cell repair

Parkin is absent or faulty in half the cases of early onset Parkinson's disease, as well as in some other, sporadic cases. In a healthy brain, Parkin helps keep cells alive, and decreases the risk of harmful inflammation by repairing damage to mitochondria, which are responsible for supplying energy to cells. Damaged mitochondria could trigger the cell's internal death machinery, which removed unwanted cells by a cell death process termed apoptosis.

"We discovered that Parkin blocks cell death by inhibiting a protein called BAK. BAK and a related protein called BAX are activated in response to cell damage, and begin the process of destroying the cell - by dismantling mitochondria. This ultimately drives the cell to die, but low-level mitochondrial damage has the potential to trigger inflammation - warning nearby cells that there is potential danger."

The team showed that Parkin restrains BAK's activity when mitochondria are damaged. Parkin tags BAK with a tiny protein called ubiquitin. With normal Parkin, BAK is tagged and cell death is delayed. Parkin 'buys time' for the cell, allowing the cell's innate repair mechanisms to respond to the damage. Without Parkin - or with faulty variants of Parkin that are found in patients with early-onset Parkinson's disease - BAK is not tagged and excessive cell death can occur. This unrestrained cell death may contribute to the neuronal loss in Parkinson's disease.

Comments

It has been known since the 1950s that long-term heavy smokers have about half the rate of Parkinson's as non-smokers; it is widely believed that the nicotine is protective. Yet a search on clinicaltrials.gov finds 7 studies, at least two completed and relevant, but NONE "with results" reported on that site. (286 OTHER Parkinson studies did have results on the site.)

So it seems that we already have an example of a treatment that works in some cases - which might be a gold mine for basic researchers looking for insights into the disease mechanism, and better treatments. But somehow this example is getting much less attention that it apparently deserves.

Posted by: John S. James, @AgeTreatment at January 13th, 2019 10:10 PM

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