Tauopathies: A Distinct Class of Neurodegenerative Disorders

Abstract

General overview: Neurodegenerative diseases are characterized by neuronal loss and intraneuronal accumulations of fibrillary materials. Neuropathologists distinguish several intracellular inclusions such as Hirano bodies, Lewy bodies, Pick bodies and neurofibrillary tangles (NFT). Most are argyrophilic and NFT are the most common. They are consistently found in Alzheimer’s Disease (AD), frontotemporal dementia, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam (ALS/PDC), corticobasal degeneration (CBD), dementia pugilistica and head trauma, Down syndrome, postencephalitic parkinsonism, progressive supranuclear palsy (PSP) and Pick’s Disease. NFTs are also seen in normal aging. Neurofibrillary tangles contain hyperphosphorylated microtubule-associated protein tau, because of these characteristics these diseases are classified as “tauopathies”.

Tau gene and Tau protein: The human tau gene is unique and located over 100 kb on the long arm of chromosome 17. It contains 16 exons. In the human brain, Tau proteins constitute a family of six isoforms, which range from 352 to 441 amino acids. To date, 34 different pathogenic tau mutations have been described in a total of 101 FTDP-17 families. Depending on their functional effects, mutations on Tau proteins may be divided into two groups: the mutations affecting the alternative splicing of exon 10, and leading to changes in the proportion of 4R- and 3R-Tau isoforms, and the mutations modifying Tau interactions with microtubules.

Molecular classification of Tauopathies: Comparative biochemistry of Tau aggregates shows that they differ in both phosphorylation and content of tau isoforms, which enable a molecular classification of tauopathies. Five classes of tauopathies have been defined depending on the type of Tau aggregates. Many parameters can explain this categorization such as the selective aggregation of specific sets of Tau isoforms, the differential vulnerability of neuronal subpopulations, in addition to possibly variable sets of enzymes.

Conclusion: The data discussed indicate, that the key event in tauopathies is always the disorganization of the cytoskeleton, based on mutations/polymorphisms in the tau gene, leading to nerve cell degeneration.