A Novel Therapeutic Approach to Parkinson's Disease: Using Transcriptomics to Identify Unique Patterns of Gene Expression including 'Triple Positives,' Toll receptors, and Endotoxin Exposure

Abstract

Parkinson's disease 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. 20-40% of Parkinson's disease patients also develop dementia within 10 years of diagnosis, and 50-80% develop dementia after 15-20 years. There is no agreement on objective biomarkers to define the onset of this illness, including commercially available genomic testing, which makes early detection difficult and the identification of prodromal symptoms obscure. Neuropathology of Parkinson's Disease is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, marked by the 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 or delay symptoms, there is no cure. Even if a cure remains elusive, improving quality of life is a reasonable goal, especially if reliable biomarkers are available to diagnose illness and assess the effectiveness of therapy. This study aims to investigate transcriptomic biomarkers in a subset of Parkinson's Disease (PD) patients with prior exposure to biotoxins, particularly lipopolysaccharides (LPS) from water-damaged buildings. This paper focuses on the role of TLR2, RELA, and associated inflammatory and autophagic pathways as part of a novel model linking environmental exposure and neurodegeneration. The scope includes evaluating these markers for diagnostic and therapeutic utility in CIRS-related PD phenotypes. We recently reported transcriptomic abnormalities in a deidentified subset of patients with Chronic Inflammatory Response Syndrome characterized by a multisystem, multi-symptom inflammatory and metabolic illness due to prior or ongoing exposure to the interior environment of water-damaged buildings. A transcriptomic diagnostic test, based on mRNA expression, was applied to white blood cells called GENIE (Genomic Expression: Inflammation Explained). The use of transcriptomics provides a deeper understanding of the genomic underpinnings that mediate disease processes and the relationship between gene-environmental interactions in neurodegenerative disorders. GENIE reliably identifies features that define the specific causation of offending microbial substances in patients who produce systemic inflammation following exposure to the interior of damp buildings, where various resident toxigenic fungi, Actinobacteria, beta-glucans, and/or lipopolysaccharides (LPS, endotoxins) can be found either singly or in combination. A unique transcriptomic fingerprint was found in symptomatic Parkinson's patients in this population. The genomic grouping was represented by (i) clusterin (CLU), (ii) a panel of coagulation (COAG) genes, and (iii) cytoskeletal tubulin genes (TUB), cumulatively called Triple Positives (TP). We also showed treatment with a published protocol corrected many symptoms while restoring normal gene expression. In this current paper, we aim to expand the gene set associated with Parkinson's Disease while linking this genomically related pathophysiology to a specific exposure to lipopolysaccharides (LPS), also known as endotoxins. We present four additional genomic biomarkers combined with the prior Triple Positive findings associated with Parkinson's Disease, including patients possibly in the prodromal phase: (i) elevated numbers of cases with genes that reflect specific causation (SC) of illness; (ii) elevated levels of Toll receptor 2 (TLR2); (iii) elevated levels of Akt, focusing on autophagy; (iv) elevated levels of a nuclear transcription gene, RELA, encoding for a component of NFκB. This is the first paper to relate an expanded set of genomic biomarkers characterizing the inflammatory effects of LPS in humans, which are also observed in animals with experimental Parkinson's Disease. The prior finding of Triple Positives, combined with these four new biomarkers, creates the possibility that clinical Parkinson's Disease could be avoided if biomarkers for dysfunctional genes were identified and treated in the prodromal phase before clinical symptoms and signs of overt disease become apparent.

Key Biomarkers

Symptom Clusters