A Transcriptomic Fingerprint for Parkinson's Disease Found in Patients with Chronic Inflammatory Response Syndrome: Implications for Diagnosis, Treatment and Prevention

Abstract

Parkinson's Disease (PD) is the second most common neurodegenerative disease worldwide, characterized by a movement disorder that includes tremors, micrographia, difficulty initiating and stopping movement, stiffness, raspy voice, constipation, fatigue, anosmia, musculoskeletal pain and loss of balance resulting in significant disability, risk for infection and substantial need for care of activities of daily living. Many people with PD also develop dementia. The onset of illness usually begins during the 6^th decade of life. Neuropathology of PD is characterized by progressive loss of dopaminergic neurons of the substantia nigra marked by intracellular accumulation of α-synuclein in the form of Lewy bodies and Lewy neurites. While dopamine-promoting medications are the mainstay of treatment to reduce symptoms, there is no cure. The leading cause of death is pneumonia, and an average life expectancy is 14.5 years.

We recently reported abnormalities in cytoskeletal tubulin genes TUBA4A and TUBB1 associated with die-back of degenerative central nervous system disorders, including Alzheimer's disease, PD and amyotrophic lateral sclerosis (ALS), using a transcriptomic diagnostic test on white blood cells, based on mRNA expression, called GENIE (Genomic expression: inflammation explained). The use of transcriptomics provides a better understanding of the genomic underpinnings mediating disease expression and the relationship between gene-environment interactions in neurodegenerative disorders.

This paper reports our findings of a unique transcriptomic fingerprint, including tubulin genes, densely found in symptomatic PD patients and much younger patients with fewer symptoms. The grouping is represented by clusterin (CLU) and a panel of coagulation (COAG) genes, called "Triple Positives," consistently found in a subset of Chronic Inflammatory Response Syndrome (CIRS) patients, independent of age but invariantly linked to patients with at least three upregulated COAG genes. Treatment with a published CIRS protocol in a small study corrects many symptoms and Triple Positives, regulating normal gene expression.

This fingerprint supports reports of similar transcriptomics in the PD literature but is the first to demonstrate successful resolution of differentially expressed genes in PD using commercially available medications. Finding Triple Positives in CIRS patients younger than 50, in the absence of toxic compounds like MPTP and instead initiated by exposure to WDB, raises the possibility of neuroprotection from PD if intervention were initiated before neurodegenerative changes are underway. While many putative causes of PD have been explored, a genomically mediated model of disease initiation and expression has emerged supporting a potential paradigm shift regarding PD, . Our work offers a unified framework of environment-gene interaction in the PD population connected to contaminated indoor living spaces, which we term CIRS-PD.