TUBB1, TUBA4A and MAPK as Indicators of Die-Back Degenerative Central Nervous System Disease in Patients Sickened by Specific Exposure to the Interior Environment of Water- Damaged Buildings
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Abstract
Beginning with Possible Estuarine Associated Syndrome (PEAS) in 1998 and followed by numerous studies on similar types of exposures, patients with illness associated with biotoxin exposure routinely have had symptom rosters dominated by executive cognitive dysfunction, including recent memory deficits, difficulty in concentration, difficulty with word finding, decreased assimilation of new knowledge, confusion and disorientation, tremors, headaches, vertigo, and unusual pains. In addition, tremors, headaches, vertigo, unusual pains and metallic taste. Toxins involved variously have included those found in toxin-forming dinoflagellates, including Pfiesteria and ciguatera; cyanobacteria, including Microcystis, Cylindrospermopsis and Lyngbya wollei; post Lyme syndrome and Babesia; as well as organisms found in damp buildings, including Aspergillus versicolor and A. penicillioides, Stachybotrys chartarum, Chaetomium globosum, Wallemia sebi, Actinobacteria species, especially Corynebacteria tuberculostearicum and Propionibacterium acnes; as well as bacterial endotoxins and beta-glucans. These illnesses have been called chronic inflammatory response syndromes (CIRS).
The mechanism of neurologic findings has remained elusive despite studies showing successful treatment with intranasal vasoactive intestinal polypeptide (VIP). Neurocognitive testing has only been performed in PEAS patients, showing profound deficits in learning and higher cognitive functioning. These CIRS patients have had brain imaging without consistent findings, including MRI, EEG, and CT of the brain. NeuroQuant has shown findings that fit a “fingerprint” found in patients with specific causation and confirmed exposure to Actinobacteria and endotoxins. Fungal exposure shows disproportionate enlargement due to interstitial edema in the forebrain parenchyma and cortical grey, with a diminished caudate nucleus size. These findings have not been found in controls. The recent inclusion of transcriptomic studies using GENIE has confirmed that specific causation can be identified for Actinobacteria (48% of total confirmed cases), bacterial endotoxins (28%) and fungi (7%) in CIRS patients. The combination of NeuroQuant and GENIE has implicated excessive production of cytoskeletal tubulin genes TUBA4A and TUBB1 as risk factors for specific fingerprints for die-back degenerative central nervous system (CNS) injury in patients with illnesses associated variously with exposure to Actinobacteria, fungi and endotoxins.
This study seeks to implicate a causal abnormality of excessive expression of tubulin genes TUBA4A and TUBB1. Given the role of these genes in die-back CNS degenerative diseases, such as Alzheimer’s, amyotrophic lateral sclerosis and Parkinson’s disease, and anecdotal successful treatment of CIRS patients with elevated TUBA4A and TUBB1, we suggest the possibility of treatment of tubulin excess may have a role in clinical improvement seen in die-back CNS degenerative diseases. Elevated levels of MAPK are also risk factors when combined with elevated levels of TUBA4A and TUBBI.
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