The ganglioside GM3 synthase (SAT-I), encoded by a single-copy gene, is a primary glycosyltransferase for the synthesis of complex gangliosides. In SAT-I null mice, hearing ability, assessed by brainstem auditory-evoked potentials (BAEP), was impaired at the onset of hearing and had been completely lost by 17 days after birth (P17), showing a deformity in hair cells in the organ of Corti. By 2 months of age, the organ of Corti had selectively and completely disappeared without effect on balance or motor function or in the histology of vestibule. Interestingly, spatiotemporal changes in localization of individual gangliosides, including GM3 and GT1b, were observed during the postnatal development and maturation of the normal inner ear. GM3 expressed in almost all regions of cochlea at P3, but at the onset of hearing it distinctly localized in stria vascularis, spiral ganglion, and the organ of Corti. In addition, SAT-I null mice maintain the function of stria vascularis, because normal potassium concentration and endocochlear potential of endolymph were observed even when they lost the BAEP completely. Thus, the defect of hearing ability of SAT-I null mice could be attributed to the functional disorganization of the organ of Corti, and the expression of gangliosides, especially GM3, during the early part of the functional maturation of the cochlea could be essential for the acquisition and maintenance of hearing function.auditory system ͉ cochlea ͉ deafness ͉ knockout mice ͉ sialyltransferase G angliosides [i.e., glycosphingolipids (GSLs)] containing sialic acid are abundant in central nervous tissues and are considered to have important roles in controlling development, proliferation, differentiation, and maintenance of neural tissues and cells (1). Gangliosides usually reside in the outer leaflet of the cell membrane and are concentrated in microdomains specialized for cell adhesion and cell signaling (2, 3). The first product in the biosynthetic pathway of the ganglio-series gangliosides is GM3, which serves as a common precursor for the a-series and b-series gangliosides (Fig. 1). The sialyltransferase responsible for GM3 synthesis is the GM3 synthase (EC 2.4.99.9), also known by the names SAT-I (used here), ST3GalV, and Siat 9. The gene encoding this enzyme has been identified by several research laboratories, including ours (4-6).In the study presented here, we generated mice deficient in GM3 synthase (SAT-I Ϫ/Ϫ mice) (7) and examined their general behavior, including their motor function, learning and memory, and sensory function. Interestingly, SAT-I Ϫ/Ϫ mice exhibited no startle reflex in response to various acoustic stimulations, yet they did demonstrate normal startle responses to air puffing, suggesting a hearing impairment. Electrophysiological and histological analyses of the auditory system of the SAT-I Ϫ/Ϫ mice further revealed that the organ of Corti in the inner ear is selectively degenerated in these animals. ResultsAbsence of Acoustic Startle Response in SAT-I Null Mice. GM3 synthase null (SAT...

Neurofibrillary tangles, composed of hyperphosphorylated tau fibrils, are a pathological hallmark of Alzheimer's disease; the neurofibrillary tangle load correlates strongly with clinical progression of the disease. A growing body of evidence indicates that tau oligomer formation precedes the appearance of neurofibrillary tangles and contributes to neuronal loss. Here we show that tau oligomer formation can be inhibited by compounds whose chemical backbone includes 1,2-dihydroxybenzene. Specifically, we demonstrate that 1,2-dihydroxybenzene-containing compounds bind to and cap cysteine residues of tau and prevent its aggregation by hindering interactions between tau molecules. Further, we show that orally administered DL-isoproterenol, an adrenergic receptor agonist whose skeleton includes 1,2-dihydroxybenzene and which penetrates the brain, reduces the levels of detergent-insoluble tau, neuronal loss and reverses neurofibrillary tangle-associated brain dysfunction. Thus, compounds that target the cysteine residues of tau may prove useful in halting the progression of Alzheimer's disease and other tauopathies.

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GM3 synthase (ST3GAL5) is the first biosynthetic enzyme of a- and b-series gangliosides. Patients with GM3 synthase deficiency suffer severe neurological disability and deafness. Eight children (ages 4.1 ± 2.3 years) homozygous for ST3GAL5 c.694C>T had no detectable GM3 (a-series) or GD3 (b-series) in plasma. Their auditory function was characterized by the absence of middle ear muscle reflexes, distortion product otoacoustic emissions and cochlear microphonics, as well as abnormal auditory brainstem responses and cortical auditory-evoked potentials. In St3gal5(-/-) mice, stereocilia of outer hair cells showed signs of degeneration as early as postnatal Day 3 (P3); thereafter, blebs devoid of actin or tubulin appeared at the region of vestigial kinocilia, suggesting impaired vesicular trafficking. Stereocilia of St3gal5(-/-) inner hair cells were fused by P17, and protein tyrosine phosphatase receptor Q, normally linked to myosin VI at the tapered base of stereocilia, was maldistributed along the cell membrane. B4galnt1(-/-) (GM2 synthase-deficient) mice expressing only GM3 and GD3 gangliosides had normal auditory structure and function. Thus, GM3-dependent membrane microdomains might be essential for the proper organization and maintenance of stereocilia in auditory hair cells.