Immunophilins and Neurodegenerative Disorders

Over the past decade, considerable evidence has accrued suggesting that immuno-philin ligands display neurotrophic effects in various in vitro and in vivo systems, and that PPIase activity might be involved in neurodegenerative processes [38,39]. Use of [3H]FK506 showed that hFKBP12 levels change in neuronal diseases since they decline in dying neurons and are elevated in less severely injured neurons. In a rat model, the FKBP12 level declines markedly in the hippocampus and increases in the area of cerebral infarction following focal ischemia [40]. In comparison with normal human brain, FKBP12 distribution and levels increase considerably in several areas of the brains of patients suffering from Parkinson's disease, Alzheimer's disease, and dementia with Lewy bodies [41-43]. HFKBP12 concentrations in the central nervous system are up to 50 times those in the immune system. Recent studies have shown that hFKBP12 and hFKBP52 are also abundant in the spinal cord [44].

It is difficult to discriminate the direct effects of PPIases on neuronal proteins from their chaperone activity in maintaining the function of receptor heterocom-plexes since steroid receptors, the Ryr calcium channel, and IP3 receptors are also present in neurons. In particular, FKBP-controlled disruption of the steroid receptor heterocomplex is known to mediate neurite elongation via a "gain of function" [7,45]. The neuroregenerative activity of FK506 also involves the MAP kinase pathway, which mediates the neurotrophic activity of FK506. Moreover, hFKBP12 acts as an inhibitor of TGF-b, which causes cell cycle arrest [46].

FK506 is neuroprotective against global and focal ischemia in toxic chemical models and mechanical injury to a peripheral nerve. Its neuroprotective effects against ischemia seem to be dependent upon calcineurin inhibition but are inde pendent in nonischemic diseases since FK506-related compounds devoid of immunosuppressive activity are equally active [6-8].

The presence in many neurodegenerative diseases of neurofibrillary tangles containing a-synuclein colocalized with hFKBP12 and other molecular chaper-ones, in particular hsp70 and hsp40, suggests that the presence of intraneuronal inclusions might be related to the CTI activity of PPIases. Moreover, the presence of hFKBP12 in filamentous s lesions might be interpreted as an attempt to counteract the hyperphosphorylation of paired helical fragments usually found in neu-rofibrillary tangles [42,47].

Alzheimer's disease as well as other neurodegenerative disorders such as Pick's disease, corticobasal degeneration and supramolecular palsy are characterized by an accumulation of hyperphosphorylated s protein and subsequent formation of paired-helical fragments which form neurofibrillary tangles [8,48]. Phosphorylation of Thr231-Pro232 and Ser235-Pro236 decreases the rate of uncatalyzed trans to cis isomerization and thus reduces binding of s protein to tubulin. Therefore, s proteins become more available for aggregation as PHF. Although Pinl accelerates CTI of phosphorylated Ser/Thr-Pro sequences, its binding to the trans conformer of s protein (either via its catalytic site or a WW domain) results in sequestering of Pinl and a dramatic fall in soluble PPIase [47,49,50].

Prion diseases such as bovine spongiform encephalopathy, scrapie in sheep, kuru, and Creutzfeldt-Jakob disease, which are all characterized by irreversible aggregation of a proteinase conformer of protein PrPc (called PrPSc), might also involve CTI of one or several amino acyl prolyl sequences [8]. Residue Pro101 of the prion protein has been clearly implicated in the formation of b-sheet fibrils

[51] as well as in the model Ure2 protein isolated from Saccharomyces cerevisiae which contains a prion domain that folds very much like that ofthe prion protein

[52]. However, the exact role of PPIases in prion diseases remains unclear, though recent reports show that when cells are cultured with the immunosuppressant CsA there is accumulation of PrP-like aggregosomes resembling those of scrapie

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