What causes Parkinson's? This is one of the trickiest questions facing researchers and doctors – not to mention patients – and it's the topic being tackled by the Movers and Shakers as they take to the Notting Hill pub today. Is there something atmospheric? Or does the club lie in our DNA? Our guide through this topic is Professor Matt Farrer, one of the leading lights of this research area.
By Podot
Each week Rory Cellan-Jones guides us between the laughs and moans in the pub. To read Rory's summary of this week's episode click here.
Guest Biography
Professor Matthew Farrer
Professor Farrer’s career objective is to provide molecular targets, tools and research insights in neurologic and age-related neurodegenerative disorders, so as to encourage major pharmaceutical investment. For the past 25 years his research has been largely focused on neurogenetics and molecular neuroscience modelling of Parkinson’s disease and atypical Parkinsonism.
His mission is to make molecular diagnoses and develop disease-modifying (I hope) therapeutics aimed at neuroprotection (precision medicine).
Ongoing projects include the genetic analysis of patient DNA samples from pedigrees and population isolates by high-throughput and Sanger sequencing. In parallel, his team seeks to characterise those genes and mutations in model systems, and primarily through cre-loxP conditional recombineering of the mouse genome. Experiments are kept as physiologic as possible to help understand how gene dysfunction predicates the human condition. Prof Farrer’s team have been involved, if not responsible for, almost all major Mendelian discoveries in Parkinson’s disease research.
Prof Farrer currently directs the Laboratory of Neurogenetics and Neuroscience in the Department of Neurology at the University of Florida. He was trained in molecular and statistical genetics and neuroscience at Imperial College, London. He is also a Canada Excellence Research Laureate and Distinguished Investigator of Mayo Clinic.
Genetics - and the art of automotive engineering
An analogy from Prof. Matt Farrer, neuroscientists, geneticists and 'chief mechanic'
Much like the human brain, a car engine is complex. Should it develop a fault you'd be best off taking it to someone with a good understanding of the component parts, a diagnostics kit and, hopefully, the ability to fix it.
The go-to mechanics in the Parkinson's world are Movement Disorder Specialist neurologists. An MDS should ensure a PWP (person with Parkinson’s) gets an accurate diagnosis, provided the GP knows enough to recognise the symptoms as possibly neurological.
Still currently incurable, we've yet to work out how to fix PD but we are at last beginning to see some progress. The mystery of how Parkinson’s disease is caused, and how it impacts the engine (brain) and its molecular components has begun to be solved through genetic analysis. Each faulty gene we identify is a part of an engine. The ‘Hayes manual’ of the genetic engine is still very much a work in progress. We need to find more parts and figure out how these components work together... in order to better diagnose and repair it.
The older the car the more likely that there are several issues impacting its smooth running over time. Similarly, most late-onset Parkinson’s disease is ‘polygenic’ (poly = Greek for ‘many’) and likely to be due to the influence of many genetic variants and environmental factors. No single variant or gene can be considered ‘causal’, and none is particularly useful to any specific individual, not in any diagnostic or prognostic way. The effect of those genetic variants, singularly or in combination, is just too small. Nevertheless, identifying those genetic components is still possible and of interest as a scientific endeavour.
Genome-wide association studies (GWAS) typically require >100,000 people with/without Parkinson’s disease to take part. To date the majority have been performed in European, East Asian and Latino populations and have implicated > 92 positions (or loci) containing about 350 genes. Each locus (being the singular form of loci = Greek for ‘place’) can typically be defined by hundreds of single nucleotide polymorphism (SNPs), and that variability is associated to disease (and to each other). The influence of environment on this genetic background is likely to play an important role.
However, some genes and the variability within them can be considered more crucial than others… Back under the bonnet (or ‘hood’ for our US readership), a fault in just one component part may cause the engine to fail (e.g. a flat battery). Such variants may be considered ‘causal’ and then Parkinson’s Disease can be considered ‘monogenic’ - down to one faulty gene type. These pathogenic variants are usually identified in patients with young-onset Parkinson’s disease and/or in patients with a family history of Parkinsonism.
With such variants, the effect size is generally large enough to be diagnostically useful. Indeed, disease inheritance may follow a specific pattern down the family line, such as: ‘dominant’ - with age, half of each generation, and each preceding generation is likely to manifest disease), ‘recessive’- on average, one quarter of people in one generation will be affected, and parents are typically unaffected but are ‘carriers’ or ‘X-linked’ - typically half of the males in any generation are affected, but that pattern is generally seen in uncles and nephews, rather than fathers and sons.
In young-onset Parkinson’s Disease (YOPD) and/or patients with family history of Parkinsonism we can now identify a singular genetic problem in a fifth to a third of patients (~20-30%). There are ~7 major genes that would fulfil a diagnosis of clinical Parkinson’s Disease (see below) and perhaps twenty or more that might be considered to lead to a more atypical form of Parkinsonism. To identify new genes, not only new variants in known genes, requires just a few families with multiple affected persons to take part in a linkage study (otherwise known as a ‘disease-concordant exome’ or ‘whole genome analysis’).
The families that have taken part, so far, have played an invaluable role in moving this science on. Further involvement of patients and their families should see this area of research accelerate as we identify the missing parts of this ‘molecular machine’. Sequencing for the entire genome is available through the NHS Genomic Medicine Service, free of charge in the UK. In the USA, YOPDers and families might take part in a genome sequencing effort run by the Parkinson’s Foundation, in collaboration with the Michael J Fox Foundation and the Brin Foundation. This service is provided with genetic counselling and return of those results; with no cost to participants. However, patients have to be referred by their neurologist, and both patients and their neurologists benefit from genetic counselling if the results are to be returned.
Globally, anybody with a family history with one or more blood relatives with a diagnosis of Parkinson’s Disease can also take part in genome sequencing through the monogenic hub of GP2. This is a research project funded by the Brin Foundation that’s managed by the Michael J Fox Foundation. It is accessible to any and all collaborating neurologists around the world. Nevertheless, those results may not be returned, diagnostically, to patients, as that sequencing is not performed in a clinically-accredited manner. However, if ‘positive’ some confirmatory diagnostic testing could be sought in a clinically-accredited laboratory and returned with appropriate genetic counselling.
Before signing up, patients and their neurologists need to be aware that there are many types of genetic tests. Not all have the same resolution, and the technology to sequence and interrogate genomes is continually improving. There are also many different types of genetic variants (see ‘A genetic primer’).
A genetic primer
• Genes (in DNA and RNA) encode proteins, and proteins make cells, tissues and organisms.
• The human genome is ~3,000,000,000 (3 billion) nucleotides in length, and we have two copies (we’re diploid), a set from your dad, another set from your mum (se we each have ~6,000,000,000 nucleotides). These genomes are mostly identical except for at ~27,000,000 (27 million) nucleotides which vary from one person to another.
• There are also many copies of a mitochondrial genome of ~16,000 nucleotides in length, that is inherited from your mum.
• Nucleotides, or ‘bases’, include A (adenine), C (cytosine), G (guanine) and T (thyamine).
• The genetic code is a string of nucleotides like CAGCAGTAG, and some regions (in genetics called a locus = Greek for ‘place’ (pl. =loci)) known as genes (~1% of the whole genome) encode proteins.
• Proteins are strings of amino acids, linked in sequence, that are defined by triplets in the genetic code e.g. ‘CAG’ encodes the amino acid ‘glutamate’. There are 21 amino acids.
• Proteins are made of amino acids, that fold into a specific shape that define their function, as the building blocks of life.
• Genetic mutations include: i) single nucleotide variants (SNVs); ii) can affect several nucleotides (insertion/deletions), or; iii) can increase or decrease the copy number of larger regions, exons, or even entire genes. For more details click here.
If you would like to download a table of genes "linked" to Parkinson's disease or atypical Parkinsonism please click here.
You can find some images of the proteins encoded by those genes below.
Some useful links