Biomedical subjects

Venu M Nemani

Publications and source records attributed to Venu M Nemani.

3 recordsLinked to original sources

PubMed2005

Neural activity controls the synaptic accumulation of alpha-synuclein.

The presynaptic protein alpha-synuclein has a central role in Parkinson's disease (PD). However, the mechanism by which the protein contributes to neurodegeneration and its normal function remain unknown. Alpha-synuclein localizes to the nerve terminal and interacts with artificial membranes in vitro but binds weakly to native brain membranes. To characterize the membrane association of alpha-synuclein in living neurons, we used fluorescence recovery after photobleaching. Despite its enrichment at the synapse, alpha-synuclein is highly mobile, with rapid exchange between adjacent synapses. In addition, we find that alpha-synuclein disperses from the nerve terminal in response to neural activity. Dispersion depends on exocytosis, but unlike other synaptic vesicle proteins, alpha-synuclein dissociates from the synaptic vesicle membrane after fusion. Furthermore, the dispersion of alpha-synuclein is graded with respect to stimulus intensity. Neural activity thus controls the normal function of alpha-synuclein at the nerve terminal and may influence its role in PD.

Animals↗

PubMed2005

A combinatorial code for the interaction of alpha-synuclein with membranes.

Considerable genetic and pathological evidence has implicated the small, soluble protein alpha-synuclein in the pathogenesis of familial and sporadic forms of Parkinsons disease (PD). However, the precise role of alpha-synuclein in the disease process as well as its normal function remain poorly understood. We recently found that an interaction with lipid rafts is crucial for the normal, pre-synaptic localization of alpha-synuclein. To understand how alpha-synuclein interacts with lipid rafts, we have now developed an in vitro binding assay to rafts purified from native membranes. Recapitulating the specificity observed in vivo, recombinant wild type but not PD-associated A30P mutant alpha-synuclein binds to lipid rafts isolated from cultured cells and purified synaptic vesicles. Proteolytic digestion of the rafts does not disrupt the binding of alpha-synuclein, indicating an interaction with lipid rather than protein components of these membranes. We have also found that alpha-synuclein binds directly to artificial membranes whose lipid composition mimics that of lipid rafts. The binding of alpha-synuclein to these raft-like liposomes requires acidic phospholipids, with a preference for phosphatidylserine (PS). Interestingly, a variety of synthetic PS with defined acyl chains do not support binding when used individually. Rather, the interaction with alpha-synuclein requires a combination of PS with oleic (18:1) and polyunsaturated (either 20:4 or 22:6) fatty acyl chains, suggesting a role for phase separation within the membrane. Furthermore, alpha-synuclein binds with higher affinity to artificial membranes with the PS head group on the polyunsaturated fatty acyl chain rather than on the oleoyl side chain, indicating a stringent combinatorial code for the interaction of alpha-synuclein with membranes.

Amino Acid Substitution↗

PubMed2005

Effects of 23.4% sodium chloride solution in reducing intracranial pressure in patients with traumatic brain injury: a preliminary study.

OBJECTIVE: Mannitol is the standard of care for patients with increased intracranial pressure (ICP), but multiple administrations of mannitol risk renal toxicity and fluid accumulation in the brain parenchyma with consequent worsening of cerebral edema. This preliminary study assessed the safety and efficacy of small-volume injections of 23.4% sodium chloride solution for the treatment of intracranial hypertension in patients with traumatic brain injury who became tolerant to mannitol. METHODS: We retrospectively reviewed the charts of 13 adult patients with traumatic brain injury who received mannitol and 23.4% sodium chloride independently for the treatment of intracranial hypertension at San Francisco General Hospital between January and October 2003. Charts were reviewed to determine ICP, cerebral perfusion pressure, mean arterial pressure, serum sodium values, and serum osmolarity before and after treatment with 23.4% sodium chloride and mannitol. Complications were noted. RESULTS: The mean reductions in ICP after treatment were significant for both mannitol (P < 0.001) and hypertonic saline (P < 0.001); there were no significant differences between reductions in ICP when comparing the two agents (P = 0.174). The ICP reduction observed for hypertonic saline was durable, and its mean duration of effect (96 min) was significantly longer than that of mannitol treatment (59 min) (P = 0.016). No complications were associated with treatment with hypertonic saline. CONCLUSION: This study suggests that 23.4% hypertonic saline is a safe and effective treatment for elevated ICP in patients after traumatic brain injury. These results warrant a rigorous evaluation of its efficacy as compared to mannitol in a prospective randomized controlled trial.

Adult↗