July 6, 2015: Tauopathies
July 6, 2015
Many neurodegenerative diseases involve abnormal accumulation of the microtubule-associated protein tau. We often refer to these disorders as "tauopathies." The list is lengthy but common disorders include Alzheimer's, Down's syndrome, chronic traumatic encephalopathy, frontotemporal dementia, Pick's disease, corticobasal degeneration, and progressive supranuclear palsy. We also know that this tau accumulation is typically an age-dependent process; however, traumatic brain injuries early in life can also induce and/or expedite this phenomenon which was initially observed in boxers, inspiring the term "punch drunk," and has been studied in more recent years with athletes in high-contact sports.
While there are still many questions to be answered, we do know that tau is a protein that binds to microtubules in the CNS and likely has a role in their stabilization. It is encoded by the MAPT gene on chromosome 17 and has six isoforms. Tau is naturally in a monomeric and soluble form and when unphosphorylated, it binds microtubules, but if it is hyperphosphorylated in conjunction with inadequate phosphatase activity, it is unable to bind microtubules and accumulates pathologically in various disease-specific patterns. For example, in Alzheimer's disease, abnormal tau appears to aggregate early in the locus ceruleus. This phosphorylation pathway along with others related to tau aggregation and clearance are the targets of pharmacological research for treatments of these diseases.
- Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurology 2013; 12: 609–622.
- McKee AC, Cantu RC, Nowinski CJ, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy following repetitive head injury.” Journal of Neuropathology & Experimental Neurology 2009; 68: 709–735.
- Lee G, Leugers CJ. Tau and Tauopathies. Progress in Molecular Biology and Translational Science 2012; 107: 263–293.
- Gandy S, Ikonomovic MD, Mitsis E, et al. Chronic traumatic encephalopathy: clinical‐biomarker correlations and current concepts in pathogenesis. Molecular Neurodegeneration 2014; 9: 37.
Submitted by Sarah Wesley MD, Department of Neurology, Mount Sinai Beth Israel Medical Center.
Disclosures: Dr. Wesley is a member of the Residents & Fellows Section of Neurology.