Paired helical filament

Rather scanty evidence exists for the participation of free radicals in Alzheimer s disease and Down s syndrome. However, more recendy, reports have appeared that suggest possible free-radical involvement in the pathogenesis of these two conditions. Zemlan et al. (1989) repotted that the activity of the free-radical scavenging enzyme, SOD, was significantly increased in fibroblast cell lines derived from familial Alzheimer s and Down s patients. They hypothesized that the elevation in SOD activity observed in the Alzheimer patients supports the theory that paired helical filaments are formed by free-radical hydroxylation of proline residues. They further su ested that SOD levels might also be increased in the brains of Alzheimer s and Down s patients, and that the increase in SOD may reflect an enhanced generation of free radicals. 

Zemlan, F., Thienhaus, O.J. and Bosmann, H.B. (1989). Superoxide dismutase activity in Alzheimer s disease possible mechanism for paired helical filament formation. Brain Res. 476, 160-162. 

Schweers O, Schonbrann Hanebeck E, Marx A, Mandelkow E. Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. J Biol Chem 1994 269 24290-24297. 

FriedhoffP, Schneider A, Mandelkow EM, Mandelkow E. Rapid assembly of Alzheimer-like paired helical filaments from microtubule-associated protein tau monitored by flourescence in solution. Biochemistry 1998 37 10223-10230. 

Schweers O, Mandelkow EM, Biemat J, Mandelkow E. Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments. Proc Natl Acad Sci USA 1995 92 8463-8467. 

The paired helical filament is made of tau protein 753 Filamentous tau is hyperphosphorylated 753... 

Abundant neuritic plaques and neurofibrillary lesions define Alzheimer s disease. Plaques are extracellular deposits made of the fibrillar P-amyloid peptide. The paired helical filament (PHF) makes up the bulk of the intraneuronal neurofibrillary pathology of Alzheimer s disease, with the straight filament (SF) being a minority species. 

Goedert, M. et al. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease Identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. USA 85 4051-4055, 1988. 

Lee,V.M.-Y. etal. A68 a major subunit of paired helical filaments and derivatized forms of normal tau. Science 251 675-678, 1991. 

Von Bergen, M. etal. Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif [306QIVYK311] forming beta structure. Proc. Natl. Acad. Sci. USA 97 5129-5134, 2000. 

Kirschner, D. A., Abraham, C., and Selkoe, D. J. (1986). X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-beta conformation. Proc. Natl. Acad. Sci. USA 83, 503-507. 

Ksiezak-Reding, H., and Wall, J. S. (2005). Characterization of paired helical filaments by scanning transmission electron microscopy. Microsc. Res. Tech. 67, 126-140. 

How does the ubiquitin-proteasome pathway contribute to pathogenesis of AD. It is thought that the causative factors in AD, namely, the A/3 peptide, or the paired helical filaments (PHF) of tau protein, impair proteasome function. In in vitro experiments, A/3 peptide has been shown to inhibit the proteasome. In the brains of AD patients, proteasome function has been shown to be reduced mostly in the areas critical for... 

Pickhardt, M., Gazova, Z., von Bergen, M., et al. (2005) Anthraquinones inhibit tan aggregation and dissolve Alzheimer s paired helical filaments in vitro and in cells. J. Biol. Chem., 280, 3628-3635. 

There is also interest in the involvement of the cytoskeleton in such degenerative diseases as Alzheimer s disease (see Chapter 14) which is characterized by tangles (paired helical filaments). It seems likely that one of the microtubule-associated proteins (tau protein) is an important component of the tangles found in Alzheimer s disease. 

As illustrated in the diagram below, domain swapping can also result in indefinite polymerization to form linear supramolecular structures. These may correspond to present-day polymers of proteins such as microtubules, or they may represent abnormal structures, like the straight and paired-helical filaments in the neurofibrillary tangles observed in the brain tissue of those afflicted with Alzheimer s disease. 

M. Uchida, T. Imahori, K. r protein kinase I converts normal tau protein into A68-like component of paired helical filaments. J. Biol. Chem., 267, 10897-10901 (1992)... 

ATP -I- T-protein = ADP -I- 0-phospho-T-protein (activated by tubulin. Different from EC 2.7.1.123 Ca /calmodulin-dependent protein kinase not activated by calmodulin, cyclic nucleotides or Ca. Involved in the formation of paired helical filaments in brain. See comment on EC 2.7.1.37 protein kinase)... 

ATP 4- protein r <1, 2, 4, 5> (<5> microtubule-associated protein, enzyme can also phosphorylate human tau [1] <1> phosphorylates r and forms paired helical filament epitopes, r/Kl, K2, K3 and t/4 repeat [6] <2> enzyme can also phosphorylate bovine tau [4] <2> phosphorylates r protein into Alzheimer disease-like forms, resulting in neuronal death [7] <2> 6 isoforms of human r expressed in adult human brain [12] <2> when a / -mediated aggregated r is used as a substrate for TPKII, an 8fold increase in the rate of TPKII-mediated r phosphorylation is observed... 

Ishiguro, K. Ihara, Y. Uchida, T. Imahori, K. A novel tubulin-dependent protein kinase forming a paired helical filament epitope on tau. J. Biochem., 104, 319-321 (1988)... 

Takahashi, M. Tomizawa, K. Ishiguro, K. Takamatsu, M. Fujita, S.C. Imahori, K. Involvement of r protein kinase I in paired helical filament-like phosphorylation of the juvenile r in rat brain. J. Neurochem., 64, 1759-1768 (1995)... 

Tomizawa, K. Omori, A. Ohtake, A. Sato, K. Takahashi, M. t-Tubulin kinase phosphorylates t at Ser-208 and Ser-210, sites found in paired helical filament-T. FEES Lett., 492, 221-227 (2001)... 

Isolated microtubules always contain small amounts of larger 300-kDa microtubule-associated proteins (MAPS).330 These elongated molecules may in part lie in the grooves between the tubulin subunits and in part be extended outward to form a low-density layer around the tubule.283 309 Nerve cells that contain stable microtubules have associated stabilizing proteins.331 A family of proteins formed by differential splicing of mRNA are known as tau. The tau proteins are prominent components of the cytoskeleton of neurons. They not only interact with microtubules but also undergo reversible phosphorylation. Hyperphosphorylated tau is the primary component of the paired helical filaments found in the brains of persons with Alzheimer disease.330... 

Both amyloid plaques and the tangles of protein tau-containing paired helical filaments are typically present in Alzheimer disease. Which comes first ... 

AD is a primary degenerative dementia affecting humans as young as in their forties. The German physician Alois Alzheimer first described the disease in 1906. It is characterized by senile plaques and paired helical filaments (PHFs), and the severity of the condition directly parallels their number.63 The involvement of aluminum in this and related dementias (dialysis encephalopathy and amyotrophic lateral sclerosis — Parkinson dementia in Guam) is currently a highly contested issue in neurological research. 

Ackmann, M., Wiech, H., and Mandelkow, E. (2000). Nonsaturable binding indicates clustering of tau on the microtubule surface in a paired helical filament-like conformation./. Biol. Chem. 275, 30335-30343. 

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