Consciousness and how it got to be that way

Sunday, September 19, 2010

Lewy Body Dementia and Alpha Synuclein as a Lipid Manipulator

In terms of understanding moment-to-moment awareness, cognitive hypofunction disorders with clear genetic contributions are often uninteresting. That is, the problem is usually that the wiring isn't there, or is wrong. The reason this is uninteresting is that if you're interested in what underlies moment-to-moment consciousness, you have to look for properties of the brain that change on the same time-scale, allowing our subjective awareness to represent some of the information in the outside world.

For this reason, pharmacology often presents more research opportunities than disease states, in particular NMDA antagonists and HT2A agonists. But there is a disease state which is notorious for hour-to-hour (or more) fluctuations in cognitive status, dementia with Lewy bodies. As you can see from the linked reference, it's not yet clear whether the disease is a sub-type of Alzheimers, or a distinct condition.

Lewy bodies are alpha-synuclein plus ubiquitin inclusions that appear in neurons specific parts of the brain in disease states; the ubiquitin suggests that these are clumps of protein the neuron is trying to degrade. Their presence is not necessarily indicative that the patient had any of the additional symptoms of Lewy body dementia. Clinical Lewy body dementia is associated with symptoms above and beyond what Alzheimers patients suffer. It also has significant overlap with Parkinson's; specifically, patients exhibit both the motor decline of PD as well as REM sleep disorder. Unlike Alzheimers, onset is not insidious. Unlike either Alzheimers or PD patients and most relevant here, Lewy body dementia patients usually have recurrent visual hallucinations, and are extremely sensitive to dopaminergic- and cholinergic-modifying medications.

When we think of real-time changes to nervous systems, we usually think of information being transmitted in an electrochemically-mediated way by neurotransmitter vesicle diffusion and membrane depolarization. Membrane potentials would also be dramatically and rapidly effected by changes in lipid membrane properties, so I had considered previously whether there were proteins expressed in brain that manipulated or maintained membrane lipid contents. It's interesting that alpha synuclein a) is known to be located on the cell membrane in some fraction, b) is natively unfolded in the cytosol, c) interacts with polyunsaturated fatty acids, d) interacts with membranes correlating with serine phosphyorylation and e) still hasn't been assigned a clear function.

This is why a recent Journal of Molecular Neuroscience paper by Riedel et al at the University of Oldenburg is important. Using an oligodendroglial cell line, they demonstrated the creation of a-synuclein aggregates (in vitro Lewy bodies) both in cells that had a point mutation in a-synuclein predisposing them to aggregate formation, as well as in wild-type cells. This was done by adding DHA (by the way, an omega 3 polyunsaturated fatty acid) and then hydrogen peroxide for oxidative stress. Alpha synuclein aggregates formed both in the mutant cell line as well as in the wild type, though the mutant cells' aggregates were bigger (all compared to non-treated controls).

My hypothesis is that alpha-synuclein is responsible for lipid processing of neuronal membranes to maintain electrochemical constancy, in response to physiologically rapid (minutes to hours) changes in the environment of the cell. In addition to the specific deficits in Lewy body dementia (associated with the brain region where the Lewy bodies appear), this may also explain the rapid fluctuation in cognitive status - cell membranes are unable to respond to a changing electrochemical environment because there's a problem with the protein that controls their lipid content. When alpha-synuclein catches up or the triggering physiological change (pH, solute concentration) reverses to previous levels, the cognitive deficits may disappear.

These findings, though they show an interaction, are therefore causally backwards - here, changes to lipids are initiating aggregation. It could be that once aggregation begins, alpha-synuclein function is off-line, and any new alpha-synuclein produced by the cell gets immediately caught in the tangle and can't perform. (There's evidence that there's more than normal at the membrane in disease states.) Here are future experiments, which in my quick survey of the literature I may have missed: 1) patch clamp recordings of dopamine receptors on cells in culture with loss-of-function mutations or knockouts of alpha synuclein, especially in response to differences in charge, pH, and buffer concentration (to mimic physiologic changes in extracellular fluid). 2) Measurement of individual fatty acid chains in knockout relative to control, in terms of their incorporation into cell membranes.

I'm both excited and nervous because in the coming weeks I will be interacting with patients in the clinic who have this disease, which is why I'm motivated to understand it.

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