Stepping Over Sidewalk Cracks

Mechanics and Dynamics of Progressive Supranuclear Palsy pathways

I promised some friends I'd write up a summary of the causes and effects of PSP, and that I would do my best to avoid the jargon and esoteric concepts of the science literature on the disease. This is a work in Progress... bear with me.



             DNA, the stuff that gets passed down from parent to offspring, gives us our physical attributes by instructing the cells in the body how to behave and how to organize themselves. It resides in the cell's nucleus in highly condensed form.

    The structure of the cell can be compared to that of an egg: imagine the yolk as the nucleus, the whites as the cytoplasm, and the shell as the plasma membrane. For a mental picture of the nerve cell, picture the egg (the cell) as having short branching structures growing from it, and a long, thin rope extending from the cell. The long thin structure is the axon and the stubby branches are dendrites. Dendrites end in synapses that send and receive information, nutrients, and organelles to and from other cells. The axon also terminates in dendrites that send signals to other cells, tissues, and muscles. If you are walking, the message sent from brain to synapse, synapse to dendrite, neuron, axon, and leg muscles, makes walking, standing, running, etc., almost a fully automatic function.

    Zoom in on the cytoplasm and you would see thousands of tiny filaments that form the cytoskeleton. The cytoskeleton is the scaffolding that gives the cell its shape and rigidity.Those tiny filaments are the microtubules. The microtubules are like two long pearl necklaces twisted together into a rope. One of these long chains is made of alpha-tubulin and one of beta-tubulin. The two tubulins are the pearls on our two imaginary necklaces. Now, imagine little strings of Elmer's Glue strategically placed to hold the tubulin chains in place. These are Tau proteins.

    Follow a line along the length of the microtubule and you will see an alternating alpha-beta-alpha-beta chain. That line is a protofilament. Thirteen protofilaments form the hollow-tubed microtubule. Both types of tubulin are made of GDP protein. At the negative end of the microtubule lies the Microtubule Organizing Center (MTOC) and centriole (more on these later), and the positive end is capped by a different type of tubulin-- GTP tubulin. Motor proteins--dynein and kinesin-- "walk" along these protofilaments, carrying vesicles and mitochondria organelles (among other things) back and forth along the microtubule.

    Vesicles are "bubbles" of organelles, information, and nutrients that have passed across the dendrite's synapses to be absorbed through the plasma membrane, picked up by dynein motors to be taken toward the nucleus, while kinesin carries mitochondria from the region of the nucleus toward the dendrites to be shipped to other cells via vesicles. Vesicle membranes are made of the same stuff as the cell's plasma membrane. As a result, they are easily absorbed into the cell when they pass across the sending cell's synapse, into receptors in the receiving cell's synapse.

    You probably have started seeing a problem at this point: The microtubules serve a dual function, and as you know, multitasking is almost always an invitation to catastrophe. Its first function is that of a cytoskeleton, and second, as a "railway" for motor proteins.

    The catastrophe, though, is part of the function. In order for microtubules to support the cell shape, they must exert force against the cytoplasm to maintain a balance against pressures in the interstitial fluid outside the cell. to do this, the microtubules engage in an action of continuous shortening and lengthening called "catastrophe" and "rescue."  In the rescue, the GTP protein dimers (two molecules joined by a loose hydrogen bond) attach themselves to the beta-tubulin dimers, forming the microtubule cap. The presence of water hydrolyzes the GTP (breaks the bond), effectively transforming GTP into GDP. With no cap, the microtubule begins to disintegrate. Tau proteins are cast off. This is the catastrophe phase. New GTP dimers attach, tau proteins re-attach, and the microtubule begins to grow again in a new rescue phase.

to be continued...