Mayo Clinic's Parkinson's Disease Lab is continuing to explore:
- Clinical characterization of Parkinson's disease and related disorders
- Neuropathological examination of Parkinson's disease and related disorders
- Genetic epidemiology of Parkinson's disease
- Model systems of Parkinson's disease for therapeutic development
Global sampling effort. Genetic studies are impossible without the generous contribution of genetic material from clinical patients and deceased individuals. Each year the lab receives between 500 to 1,000 samples from the following clinics:
Dr. Ross' lab also regularly receives samples from collaborators around the world. Daily operational support includes DNA, RNA, and plasma extractions, routine screenings, and coordinating sample logistics with diverse collaborators. The two pie charts on this page present quick visual summaries of the lab's Parkinson's disease samples by country in our series (graph 1) and the types of neuropathologically confirmed parkinsonian diseases in our series (graph 2).
- Genetic factors influencing neurodegenerative disease risk and onset, and pathology progression: genome-wide, common, single genetic variables. Each individual carries a unique 3.2 billion base-pair genome that is comprised of patterns of changes across the sequence. These patterns can result in major or minor changes to protein function, which influence aging. Studies in this area involve assessing entire genomes from thousands of individuals to identify if any variation at single genetic positions influence disease risk, age of disease onset, or pathology progression rates. In our group, we have a particular interest in investigating this in parkinsonian disorders.
- Microtubule-associated protein tau (MAPT) in parkinsonism. Haplotypes are large blocks of genetic information that are inherited between individuals and can change the structure of genes and ultimately, alter protein shape and influence protein aggregation rate. Different haplotype patterns, particularly in a gene called MAPT that codes for protein tau, influence risk of developing specific tauopathies (a group of neurodegenerative diseases) such as Alzheimer's disease, and can affect the rate and pattern at which disease pathology develops. Studies in this area involve assessing hundreds to thousands of peoples' genomes for different haplotype patterns and evaluating their roles in influencing disease type and progression rate.
- Mitochondrial genetic variation. The mitochondrial genome is less than 1% of the size of the nuclear genome, but it is present in many copies per cell, which means there is a higher likelihood of genetic variation between individual copies. As the mitochondrial genome codes for proteins that control metabolic rate, we are interested in evaluating how mitochondrial DNA variation influences disease by altering cellular metabolic efficiency. Mitochondrial genetic variation is assessed in a similar manner to the nuclear genome, whereby single position changes and haplotype changes are examined in each molecule, as well as across all molecule copies, to identify how metabolic background drives disease, as well as in the presence or absence of nuclear genetic risk factors.
- Characterizing variation of GBA in synucleinopathies. GBA mutations are one of the most well-established genetic risk factors for Parkinson's disease, Lewy body dementia and Lewy body disease. The GBA gene encodes for the lysosomal enzyme beta-glucocerebrosidase, which has been shown to increase synuclein accumulation when not functioning properly. Dysfunction in the lysosomal pathway has been linked to multiple neurodegenerative diseases. In order to characterize the variation that exists within GBA, several of our synucleinopathy series have been screened for all coding variants in the gene. This is an ongoing sequencing evaluation due to the presence of both common and rare mutations, with highly variable penetrance found in GBA. Characterizing the variation in GBA will aid in elucidating pathological mechanisms influencing disease etiologies, for which GBA mutations are a known risk. Additionally, discovery of specific mutations may give way to targetable therapies and treatment plans as we move closer to an individualized medicine model.
- Investigating familial forms of Parkinson's disease using next-generation sequencing (NGS). Genetic studies of Parkinson's disease over the years have identified multiple genetic risk loci and mutations causing both sporadic, as well as familial, forms of Parkinson's disease, such as LRRK2 and SNCA. As next-generation sequencing continues to evolve with technological advances, geneticists continue to improve data analysis strategies using exome, long- and short-read whole-genome, and single-cell sequencing technologies to identify the causative genetic mutations responsible for Parkinson's disease in many unrelated families. The importance of studying families in genetic studies is to identify inherited genetic mutations between family members that may be causing disease, which can then be screened in the larger population of sporadic Parkinson's disease. This further strengthens our understanding of this multifactorial disease.
- Nonhuman genetics in neurodegeneration. As humans are continually exposed to pathogens through life, individuals are open to contact with alien genetic material that can manipulate host biological balance. In particular, viral genetic material can integrate into host DNA and alter its machinery. Studies in our group aim to explore the presence of nonhuman genetic material in neurodegenerative diseases, and how that foreign material can alter host machinery to induce disease onset and influence disease progression with age.
- Nongenetic factors influencing disease risk, onset and pathology progression. In addition to genetic factors, lifestyle choices (particularly diet, exercise, and medication) influence ageing and disease risk. We are particularly interested in evaluating how the composition of bacterial and viral populations in your gut, called your microbiome, influences disease risk and progression. Lifestyle choices alter the composition of your microbiome, and by assessing microbiome composition over a period of time, we hope to identify microbiome factors that influence disease risk and progression, as well as lifestyle factors that alter your microbiome populations. From identifying nongenetic factors involved in disease risk and progression, we hope more noninvasive measures can be introduced clinically to prevent individuals from developing disease or can be used as a therapy to slow disease progression.
- Developing biomarkers using ultrasensitive real-time quaking-induced conversion (RT-QuIC) technology for Parkinson's disease, and other neurodegenerative diseases. The real-time quaking-induced conversion (RT-QuIC) assay is a highly sensitive test for the detection of prions and other misfolded proteins, such as alpha-synuclein and tau, which are hallmarks in neurodegeneration. This assay has evolved from a prion protein misfolding mechanism whereby normally folded proteins get converted into misfolded proteins based on the seeding phenomena from the sample being tested. The misfolded proteins are then fluorescently labeled and quantified in real time. The Centers for Disease Control and Prevention (CDC) uses RT-QuIC results in its diagnostic criteria for the probable diagnosis of human prion diseases, such as sporadic Creutzfeldt-Jakob disease (sCJD). The RT-QuIC has great potential to be clinically useful for the development of biomarkers for Parkinson's disease and related disorders, such as dementia with Lewy bodies and Alzheimer's disease.
- Investigating the molecular mechanisms of pathological genetic risk variants in Parkinson's disease using brain organoids (mini-brains) sourced from patient-derived stem cells. The human brain is an incredibly complex organ to model in neuroscience research, and animal models (predominantly rodents) have been used as surrogates to understand the human brain. However, human brains are much more complex than rodent brains, and therefore rodent models and ex vivo brain slice models do not always replicate that of the human brain. A recent major breakthrough in tissue engineering enabled scientists to overcome this limitation to modeling human neurological diseases through the development of brain organoids (commonly referred to as mini-brains). These 3D mini-brains are complex and are commonly derived from human pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells. The modeling of these organoids still has limitations, including the absence of microglia, vasculature and lack of developing body axis, but these organoids currently serve as a closest relevant model to the human brain. In Dr. Ross' laboratory, organoids are being used to better model the role of genetic variation in Parkinson's disease onset and pathology development.