Tauopathies: A Distinct Class of Neurodegenerative Diseases

Abstract

Tauopathies: A Distinct Class of Neurodegenerative DiseasesNeurodegenerative diseases are characterized by neuronal loss and intraneuronal accumulation of fibrillary materials, of which, neurofibrillary tangles (NFT) are the most common. Neurofibrillary tangles also occur in normal aging and contain the hyperphosphorylated microtubule-associated protein tau. A detailed presentation is made of the molecular bases of Alzheimer's disease (AD), postencephalitic parkinsonism, amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease, frontotemporal dementia (FTD), Down's syndrome, myotonic dystrophy (DM) and Niemann-Pick Type C (NPC) disease, which are considered to be common tauopathies. The unique human tau gene extends over 100 kb of the long arm of chromosome 17 and contains 16 exons. The human brain contains six tau isoforms that contain from 352 to 441 amino acids. To date, 34 pathogenic tau mutations have been described among 101 families affected by FTD with parkinsonism linked to chromosome 17 (FTDP-17). These mutations may involve alternative splicing of exon 10 that lead to changes in the proportion of 4-repeat- and 3-repeat-tau isoforms, or may modify tau interactions with microtubules. Tau aggregates differ in degree of phosphorylation and in content of tau isoforms. Five classes of tauopathies have been defined depending on the type of tau aggregates. The key event in tauopathies is the disorganization of the cytoskeleton, which is based on mutations/polymorphisms in the tau gene and lead to nerve cell degeneration. In this review, tauopathies as a distinct class of neurodegenerative diseases are discussed with emphasis on their molecular pathology and genetics.

Sustained high levels of neuroprotective, high molecular weight, phosphorylated tau in the longest-lived rodent

“…For example, recombinant 4R2N human tau protein has a molecular weight of 45.9kDa, while the heavily phosphorylated pathogenic tau protein extracted from AD patient brains is 72/74kDa (for review (Ozansoy, 2007)). To assess the contribution of phosphorylation on the developmental increase in tau molecular weight we probed brain homogenates with antibodies specific to tau phosphorylation before and after the addition of phosphatase (Fig.…”

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder

“…CSPα/HSP70/SGT chaperone system, which maintains SNAP25 in a functional conformation, and α-synuclein, a small SV interactor that controls synaptobrevin 2, are causally involved in neurodegenerative disorders (13)(14)(15); (d) variants of genes encoding the RIM interactor PNKD or the SNAP25 and synaptotagmin interactor PRRT2 lead to dyskinesia (16)(17)(18); and (e) a variant of the gene encoding synaptotagmin 1, the Ca 2+ sensor required for evoked, synchronous SV fusion, was recently identified in a patient with motor and cognitive impairments (19). Beyond these examples, genome-wide association studies and analyses of gene copy number variations and of single-nucleotide polymorphisms in patients suggest a link between the dysfunction of presynaptic proteins and multiple neurological and psychiatric disorders (20)(21)(22)(23)(24).…”

Search for excited electrons throughγγscattering

“…This study is a continuation of previous searches for excited electrons with spin-1=2 [9,21]. In Sec.…”