Parkinson’s Disease: What we are learning

What we know about Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra region of the brain, which leads to the progressive degeneration of the basal ganglia. The exact cause of it is not fully understood, but it is believed to result from a combination of genetic and environmental factors.

The primary pathological feature of PD is the formation of intracellular inclusions known as Lewy bodies in the remaining dopaminergic neurons. These Lewy bodies are composed of aggregated proteins, including alpha-synuclein, which accumulate in the neurons and disrupt their normal functioning.

The loss of dopaminergic neurons in the substantia nigra leads to a depletion of dopamine in the striatum, a key area of the brain involved in the regulation of movement. This results in the characteristic motor symptoms of PD, including tremors, rigidity, bradykinesia (slowness of movement), and postural instability.

In addition to motor symptoms, PD can also cause non-motor symptoms, including cognitive impairment, depression, sleep disorders, and autonomic dysfunction. The progression of disease varies from person to person, but it typically worsens over time and can lead to significant disability.

Genetics are playing a large part

In the last 3 decades, advances in research have led to great understanding about Parkinson’s disease and how the disease progressed. Several genes have been definitively linked to PD:

SNCA

This gene, which makes the protein alpha-synuclein, was the first gene identified to be associated with Parkinson’s. Research findings by the National Institutes of Health (NIH) and other institutions prompted studies of the role of alpha-synuclein in PD, which led to the discovery that Lewy bodies seen in all cases of PD contain clumps of alpha-synuclein. This discovery revealed the link between hereditary and sporadic forms of the disease.

LRRK2

Mutations in LRRK2 were originally identified in several English and Basque families as a cause of a late-onset PD. Subsequent studies have identified mutations of this gene in other families with PD (such as European Ashkenazi Jewish families) as well as in a small percentage of people with apparently sporadic PD. LRRK2 mutations are a major cause of PD in North Africa and the Middle East.

DJ-1

This gene helps regulate gene activity and protect cells from oxidative stress and can cause rare, early forms of PD.

PRKN (Parkin)

The parkin gene is translated into a protein that helps cells break down and recycle proteins.

PINK1

This gene codes for a protein active in mitochondria. Mutations in this gene appear to increase susceptibility to cellular stress. PINK1 has been linked to early forms of PD.

GBA (glucocerebrosidase-beta)

Mutations in GBA cause Gaucher disease (in which fatty acids, oils, waxes, and steroids accumulate in the brain), but different changes in this gene are associated with an increased risk for Parkinson’s disease as well.

How is research linking PD to our gut?

Braak’s hypothesis that non-familial forms of PD start in the gut by a pathogen is gaining increasing support. With accumulating evidence implicating the gut as an origin of PD, and the newly gained appreciation for the involvement of gut microbiome in chronic diseases, there has been increasing interest in decoding the connection between the gut microbiome and PD. Researchers from the University of Alabama at Birmingham have hypothesised that the gut microbiome is involved in the pathogenesis of PD through multiple pathways, including through an imbalance in microbiome composition. The researchers analysed the genetic material from the stool microbiome of 490 people with PD and 234 healthy controls. They discovered that of the 257 species of organisms in the microbiome, 84 were associated with PD, and over 30% of the microorganisms and bacterial genes tested had altered abundances in PD. This indicated a widespread imbalance in the Parkinson’s metagenome. The investigators discovered overabundance of opportunistic pathogens and immunogenic components, which suggested infection and inflammation, overproduction of toxic molecules, overabundance of the bacterial product curli, which induced PD pathology and dysregulation of neurotransmitters, including L-dopa. However, there was a shortage of neuroprotective molecules and anti-inflammatory components, making recovery difficult.

The researchers enrolled subjects who were predominantly older than 50 and from the Deep South region of the United States to eliminate the confounding effect of geographic and cultural influence on the composition of microbiomes. This study is the largest microbiome study conducted to date at the highest resolution, and the researchers made the data public, which can be used in a wide range of studies. Parkinson’s disease is a progressively debilitating disorder that affects 4 million individuals, projected to double to 8.7 million individuals by 2030. The researchers anticipate having the tools and analytic power to use metagenomics as a new approach to study PD heterogeneity, search for biomarkers, delve deeper into the origin and progression of PD sub-phenotypes, and investigate the potential of manipulating the microbiome to prevent, treat, and halt the progression of PD.

Or Is it a protein defect?

A new study by researchers at the Francis Crick Institute, University College London (UCL) and the University of Edinburgh has found that there may be some correlation in misfolded proteins that cause nerve cell death in Parkinson’s disease. The team developed a new sensitive approach to study what happens to alpha-synuclein during the earliest stages of the disease. Using neurons derived from cells donated by people with inherited forms of Parkinson’s, as well as from healthy individuals, the team were able to start to visualise where, why and how the protein starts to misfold and clump inside nerve cells. They discovered that alpha-synuclein contacts the membranes, or linings, of structures within nerve cells. They found that when it contacts the membrane of the mitochondria, part of the cell responsible for generating energy, this triggers a misfolding and clumping of alpha-synuclein. The clumps of protein then collect heavily on the surface of the mitochondria, which can lead to damage to its surface, causing holes to form on the membrane and interfering with the mitochondria’s ability to create energy. Eventually, this can lead to the mitochondria releasing signals that cause the neuron to die.

The innovative new method the researchers developed could also be used to study how proteins misfold in other neurodegenerative diseases and types of cells, including glial cells, which are involved in neurodegenerative diseases. Using their new approach, they will be able to test new therapies that aim to reduce protein misfolding and see whether these therapies can return a diseased cell to health. The study provides unique insight into a key biological process driving Parkinson’s and sheds light on the very earliest events in the disease’s development, processes that are only visible using extremely sensitive detection approaches.

World Parkinson’s Day 2023

This year on Tuesday, 11th April, we celebrated Parkinson’s Disease Day, a day marking awareness and new research helping work towards a cure for all. This day is not just a reminder of the challenges faced by individuals with Parkinson’s but also a call to action to show our support and stand by them. Australians have a unique opportunity to come together, learn, and empower each other to improve the lives of those affected by Parkinson’s. By taking part in support groups, engaging in physical exercise, and participating in social activities, we can help reduce isolation and create a sense of community that is vital to those living with Parkinson’s.

Let’s show our support for those affected by Parkinson’s by starting meaningful conversations about the disease, its impact on individuals, caregivers, and families. By doing so, we can create a more inclusive and understanding society, and most importantly, show that there is hope for a brighter future. 

Wallen et al. Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms. Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-34667-x

Choi et al. Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity. Nature Neuroscience, 2022; DOI: 10.1038/s41593-022-01140-3