LSIPR 50 2018: A decade in the making, a Parkinson’s breakthrough

Parkinson’s disease affects 127,000 people in the UK. With the prevalence of the disease becoming more common with increasing age—around five in 1,000 over 60-year-olds, and around 40 in 1,000 over 80-year-olds are affected, according to charity Age UK—it’s predicted to become an increasing burden on the population and the health services.

A study undertaken by scientists from the University of Cambridge, University of Hertfordshire and Imperial College London found that in 2010, disorders of the brain, including dementia, stroke and mental health issues, cost the UK around £112 billion ($157.3 billion) annually, with Parkinson’s disease picking up a tab of £2 billion.

Parkinson’s disease has many potential symptoms, including involuntary shaking of parts of the body. As the disease progresses, cognitive and behavioural symptoms may also develop.

Despite the prevalence and growing cost of the disease, there’s no clear understanding of what causes Parkinson’s and, according to the University of Dundee scientists, funding for Parkinson’s and other neurodegenerative diseases has traditionally lagged behind that of other disease fields.

In 2016, then UK Prime Minister David Cameron enabled the Medical Research Council to establish a £250 million Dementia Research Institute. With £150 million of funding from the UK government, and £50 million each from the Alzheimer’s Society and Alzheimer’s Research UK, the institute has set out to investigate Alzheimer’s and related disorders, including Parkinson’s in six universities across the UK (not including Dundee).

“With changing demographics the projected impact of these diseases on human health and the global economy has led to greater impetus to tackle these diseases,” explains Dr Miratul Muqit, Wellcome Trust senior clinical fellow and consultant neurologist in the University of Dundee’s school of life sciences.

Daan van Aalten, professor of biological chemistry at the school, adds that there’s an increasing presence of Parkinson’s charities including the Michael J Fox Foundation, a major player in funding Parkinson’s research worldwide.

“It is critical that pharmaceutical companies also continue to contribute to the research landscape of neurodegeneration,” he says.

Until now, the landscape has been a “graveyard for drug discovery”, notes van Aalten, which has led some companies (including Pfizer) to pull out of neuroscience altogether.

But new companies dedicated to finding cures for neurodegenerative disorders are filling the gap, explains van Aalten, citing Denali Therapeutics as an example. Denali is leading an “exciting” trial in Parkinson’s that is testing leucine-rich repeat kinase 2 inhibitors.

“The lack of neuroprotective therapies represents a significant unmet need in the management of Parkinson’s disease,” says Muqit, adding that since the causes of the disease are little understood, there’s an opportunity for “fundamental biological research to derive new knowledge for developing better treatments”.

A major breakthrough

In October 2017, the University of Dundee announced a major breakthrough. Led by Muqit and van Aalten, a team identified the structure of a key enzyme that protects the brain against Parkinson’s disease.

Previous genetic studies had revealed that inherited mutations of PINK1 cause Parkinson’s disease.

PINK1 is a class of enzyme known as a protein kinase that adds phosphate groups to protein targets (substrates) and alters the function of the substrate, a process known as phosphorylation, says van Aalten.

The enzyme has two known substrates, Parkin (another Parkinson’s gene) and ubiquitin. According to the scientists, PINK1 is the only known kinase that can target ubiquitin and it also contains several unique “floppy” structural elements.

The Dundee team, and others, have been trying to understand the structure of this enzyme for nearly a decade and there’s been a lot of interest in understanding how PINK1 targets its substrates and how mutations disrupt this.

Muqit says: “Solving the structure provides deep insights into why patients with mutations develop Parkinson’s and also provides a framework on which to develop drugs targeting PINK1 as a potential therapy in Parkinson’s.”

The scientists sought to solve the structure of an insect version of PINK1—this proved easier to study than its human counterpart.

By solving the structure of PINK1, they could visualise how patient mutations “disabled” the enzyme activity, explains van Aalten.

“We also could see how one of the flexible loop regions of PINK1 played an important role in recognising and binding to its substrates to enable it to be modified by PINK1 activity,” he says.

The insect structure can now be a stepping stone for starting to work on the human enzyme.

Although switching on enzymes as a therapeutic strategy is “extremely challenging and risky”, the structural breakthrough on PINK1 is likely to motivate companies to attempt this, states Muqit.

He adds: “We are thinking along these lines and beginning to interact with interested companies, although we are probably many years away from achieving it.”

What was the key ingredient in their success?

“Collaboration. Miratul and I have different backgrounds and expertise, and I am convinced neither of us alone could have done this,” says van Aalten.

He explains that, on the one hand, understanding PINK1 represents a neurobiological question. On the other, to obtain deep insights into its protein function, fundamental structural biology and biochemistry approaches were required.

Top ranking

The University of Dundee was ranked top in the UK for biological sciences at the last Research Excellence Framework assessment in 2014, and Ninewells Hospital in Dundee, where the university’s school of medicine is located, is one of Europe’s largest teaching hospitals.

According to the two scientists, the key to Dundee’s success is that it provides one of the best and most collaborative research environments in the world.

“A simple statistic bears this out—once people come here they tend not to leave. I myself started here in 1999 as a 28-year-old,” says van Aalten. “More than 18 years later I am still here, despite having had several opportunities to move.”

Muqit joined the university after having trained in major hospitals in London. He’s been at the university for about a decade.

In 2016, the university announced renewed funding of more than £7 million from GSK, Boehringer Ingelheim and Merck Serono to support its Division of Signal Transduction Therapy (DSTT).

Founded in 1998, the DSTT provides a platform through which Dundee researchers and pharmaceutical companies can work together to start and accelerate early stage development of new drugs.

This represents the world’s longest running collaboration between academic research laboratories and the pharmaceutical industry, says Muqit, a man who is fully aware of the benefits of teamwork in the life sciences arena.