Parkinson's disease

EXTRA INFORMATION

Improving the diagnosis and treatment of Parkinson’s

WHAT WE KNOW

Symptoms

Symptoms of Parkinson’s disease are caused by a gradual deterioration and death of brain cells in the substantia nigra. However, people with Parkinson’s can lose up to 70% of susceptible brain cells and go on for many years before symptoms become noticeable.

While symptoms vary from person to person, the most well-known symptom is a tremor. People with Parkinson’s disease may also experience slowness of movement, stiffness, a loss of automatic movements such as blinking and smiling, changes in speech and, in the later stages of the disease, dementia.

Common causes

While no one currently knows what causes brain cells to die in Parkinson’s disease, we do know that some factors increase your risk of developing this disorder. These factors include older age, living in a rural environment, being a non-smoker and exposure to some herbicides and pesticides.

Although in rare cases Parkinson’s disease can be inherited, the vast majority of cases of Parkinson’s disease are not. Nevertheless, having a family history of Parkinson’s can increase the risk of developing it, probably though genes that increase vulnerability to this disorder.

It is currently thought that Parkinson’s disease results from a complex interaction between many factors, some of which are inherited and some of which are environmental.

About our research

Because much of the damage to the brain in Parkinson’s disease occurs over several years before symptoms become noticeable, early diagnosis is a critical issue, particularly as more effective treatments become available. The Halliday laboratory is assessing tissue from people with genes known to predispose them to Parkinson’s disease, and assessing early changes in human cells in laboratory cultures using new methods to understand these early preclinical changes.

The most common disease that is misdiagnosed as Parkinson’s disease is multiple system atrophy, and both diseases abnormally accumulate the alpha-synuclein protein in their brain. The main difference is that in Parkinson’s disease the protein accumulates in neurons, while in multiple system atrophy it accumulates in their supporting cells, the glia. The Halliday laboratory is trying to understand what underlies these differences.

What we have discovered:

  • Identified how the proteins cause cellular changes
  • Discovered how LRRK2 mutations affect cells
  • Published the first assessment of progression of changes to a-synuclein identifying early phosphorylation prior to aggregation and confirmed no significant increase in the amount of soluble protein.
  • Identified glia as important in the progression of pathology.
  • Identified that dopamine terminal loss in the caudate nucleus and putamen occurs rapidly over the 1st 5 years of Parkinson’s disease.
  • Identified that reduced glucocerebrosidase (GCase) increase the risk of developing PD even in people without mutations in GBA1 gene. This occurs is prior to α-synuclein accumulation and relates to reduced chaperone-mediated autophagy, increased α-synuclein and decreased ceramide, identifying therapeutic targets.
  • Patented in vivo screen for new drug class for Parkinson’s disease – LRRK2 kinase inhibitors.
  • Developed the first selective inhibitor of LRRK2 kinase activity and made available worldwide.
  • Performed a clinical study aimed at translation of patented LRRK2 inhibitor screen for potential use in clinical trials.

Current projects

A major focus of our work is trying to understand how differences in a person’s genetic makeup can render them more susceptible to Parkinson’s disease. We are using these susceptibility genes to try to identify new therapeutic targets and earlier disease diagnostic markers.

Phosphorylation of proteins is important for the pathology in Parkinson’s disease. We are studying human-induced pluripotent stem cells to determine how such changes can produce similar disease in these cell models.

The spreading of the pathology in the brain is also important to understand and stop. Further research on the mechanisms of protein spreading will be performed, and particularly how the glia are involved.

Another aspect of our research relates to the fact that the human brain is extremely rich in lipids and that lipids are important in brain function. However, the role of lipids in the pathological processes of parkinsonian syndromes is fundamentally unknown. We will continue to study how lipids regulate alpha-synuclein aggregation process in parkinsonian syndromes with the aim of identifying molecular targets that could be exploited to control alpha-synuclein pathology in parkinsonian syndromes.

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