Biomedical subjects

R Azimova

Publications and source records attributed to R Azimova.

3 recordsLinked to original sources

PubMed2004

Amyloid peptide channels.

At least 16 distinct clinical syndromes including Alzheimer's disease (AD), Parkinson's disease (PD), rheumatoid arthritis, type II diabetes mellitus (DM), and spongiform encephelopathies (prion diseases), are characterized by the deposition of amorphous, Congo red-staining deposits known as amyloid. These "misfolded" proteins adopt beta-sheet structures and aggregate spontaneously into similar extended fibrils despite their widely divergent primary sequences. Many, if not all, of these peptides are capable of forming ion-permeable channels in vitro and possibly in vivo. Common channel properties include irreversible, spontaneous insertion into membranes, relatively large, heterogeneous single-channel conductances, inhibition of channel formation by Congo red, and blockade of inserted channels by Zn2+. Physiologic effects of amyloid, including Ca2+ dysregulation, membrane depolarization, mitochondrial dysfunction, inhibition of long-term potentiation (LTP), and cytotoxicity, suggest that channel formation in plasma and intracellular membranes may play a key role in the pathophysiology of the amyloidoses.

Amyloid↗

PubMed2000

Polyglutamine-induced ion channels: a possible mechanism for the neurotoxicity of Huntington and other CAG repeat diseases.

CAG repeats resulting in long polyglutamine tracts have been implicated in the pathogenesis of at least eight neurodegenerative diseases including Huntington. Expression of polyglutamine repeats is required for disease and increasing length of the repeats leads to earlier onset of illness (anticipation). Expression of polyglutamine repeats in cultured neurons leads to deposition of intracellular aggregates resembling those found in amyloid diseases, and to neurotoxicity. We report here that polyglutamine can induce large (19-220 pS), long-lived, (lifetime = 6 sec), non-selective (P(cation) = P(anion)) ion channels in planar phospholipid bilayer membranes, and that channel formation is enhanced by acidic pH. We propose that channel formation may be a mechanism of cellular toxicity in Huntington and other CAG repeat disease.

Huntington Disease↗

PubMedDate not supplied

The channel hypothesis of Huntington's disease.

Extended tracts of polyglutamine (PG) have been implicated in the pathogenicity of the mutant protein huntingtin and have been shown to form ion channels in planar lipid bilayers. These lines of evidence suggest that huntingtin and other PG mutant proteins may damage cells via a channel mechanism. This mechanism could cause damage to the plasma membrane by running down ionic gradients, discharging membrane potential; or allowing influx of toxic ions such as Ca(2+). PG damage to intracellular membranes such as the lysosomal membrane or the mitochondrial membrane could also injure cells via leakage of toxic enzymes or triggering of apoptosis. The channel mechanism is well-established for microbial toxins, and the existence of at least six other "amyloid" channels relevant to diseases such as Alzheimer's and Creutzfeld-Jakob, suggests that this may be a widespread pathogenic mechanism.

Humans↗