3 MYELIN SHEATH AND THE P2 PROTEIN
In this part of the Thesis we focus on a central part of the nervous system. The myelin sheath is the membrane layer that surrounds the axons transmitting neural signals across the body. A major component of this specific type of membrane is the peripheral membrane protein P2, which is a member of the fatty-acid binding protein (FABP) group. The Papers I-III presented in this Thesis, conducted in col- laboration with an experimental group, have provided new insight on the dynamics of the P2 protein, its function in the myelin sheath and how certain point mutations can be the root of many nervous diseases. In this chapter, we present an overview on the structure and function of the nervous system and the myelin sheath surrounding its axons, introduce the P2 protein, and discuss the many different diseases affecting the nervous system.
Dendrite
Cell body
Node of Ranvier
Axon terminal
Schwann cell Myelin sheath
Nucleus
Figure 3.1 A schematic drawing of the structure of a neuron. The axon emerging from the cell body is segmentally covered by the myelin sheath. The axon termini generally connect to the dendrites of another neuron or muscle cells. Figure modified from Ref. [57].
Cellular structure
The basic elements of the nervous system are the nerve cells or neurons (see Fig.
3.1). They can be divided into two regions: the cellular body (soma) and branching neuronal processes called dendrites and axons. The soma contains the basic elements of any cell, but its size and form vary depending on its location inside the nervous system. The nucleus is the source of the RNA produced in neurons required for the protein translation process. The cytoplasm contains a large number of ribosomes and the endoplasmic reticulum required for protein synthesis. The large number of mitochondria ensure that the energy requirements for the neuron are met. The Golgi complex is also present, its function being to modify and package the various proteins and enzymes that are used by the cellular body.
Branching from the cellular body are the dendrites and axons. Dendrites are short, branching extensions protruding from the cell surface. Their main function is to receive the impulses coming from other neurons and transmit them forward to their host cell body. One of the dendritic branches will be connected to an axon at an area called the axon hillock. The axon, or nerve fiber, is a long projection of a nerve cell responsible for conducting the electrical impulses known as nerve signals from one neuron to another. The length of axons may vary from millimeters to over
a meter within the spinal cord. Axons typically branch both at right angles at their length as axon collaterals, and at their termini forming numerous axon terminals which permit a single axon to make contact with multiple neurons or other cells such as muscle cells. These contact points are called synapses and are the locations of ion or ligand exchange between neurons, electrical or chemical in nature.
Each nerve cell can contain multiple dendrites, but only one axon, highlighting its importance in proper function of the nervous system. Most axons are surrounded by a thick, multilamellar membrane structure called the myelin sheath. The myelin sheath begins from the axon hillock and ends at the axon terminal, with small gaps here and there called nodes of Ranvier. The main functions of the myelin sheath are to both protect the axons from outside damage and to insulate them from their surroundings in order for faster nerve signal propagation. A thicker myelin sheath often results in better insulation and therefore a faster signal. Axon thickness is also directly related to the conduction velocity of the signal. As a result, the thickness of an axon varies depending on its location while remaining constant along its length excepting the nodes of Ranvier.
In addition to the nerve cells, the nervous system is also a host to multiple other cell types with their own functions. The glial cells are a group of several different cell classes that mainly glue the nervous system together providing them support, insulation and protection. In addition, they also support the neurons with other functions such as regulating the chemical content of the fluid outside the neurons, providing nutrients to neurons, or aiding in sustaining the integrity of the myelin sheath. [58]
Nerve signals
Information is transferred between nerve cells through electrical signals. The inside of a nerve cell has a slight negative charge due to the proteins and ions located in the cytoplasm. The charge is sustained by a number of membrane proteins located in the outer membrane of the cell acting as ion channels allowing sodium and potassium ions to enter and exit the cell interior at a controlled rate. The charge difference between the cytoplasm and the extracellular area causes a potential difference across the membrane of the neuron. The typical resting potential in a neuron is around
−70 millivolts.
A nerve signal is generated when a sudden disturbance changes the resting poten- tial across the neuron membrane. This happens when the ion channels on the neu- ron surface open and allow a large amount of positively charged ions to pass into the cytoplasm. As a result, the cell interior becomes less negatively charged. Once the potential difference across the membrane reaches the threshold potential of around
−55 millivolts, a radical change in the voltage difference can be seen. For a short period of time, the charge of the neuron interior becomes positive compared to the extracellular area with a potential difference of about+40 millivolts. This abrupt change is called the action potential. After the sudden change, which lasts for about a millisecond, the potential quickly reverses back to even higher negative values than the resting potential. After a short refractory period, during which a nerve cell can not be excited to generate another action potential, the potential difference swiftly returns to its resting state. As a result, action potentials are only very short pulses often referred to as all-or-nothing electrical outputs of a neuron.
The potential differences happen only at small parts of the membrane of the nerve cell at a time, but the generation of an action potential at one location changes mem- brane permeability around that part of the membrane. This change allows the action potential pulse to rapidly propagate along the membrane surface of an axon towards another nerve cell. The propagation of the action potential is basically the nerve signal as we know it. This active method preserves the strength of the nerve sig- nal making it a very effective way of transmitting information. If the signal would only be generated at one location, it would progressively weaken as a function of distance. Upon reaching the target synapse, the action potential passes through to the next nerve cell either through a rapid, but simple electrical transmission or by a slower, but more intricate chemical transmission.
Regions of the nervous system
The human nervous system can be anatomically divided into two main regions: the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and the spinal cord, and the PNS are all the nerves connected to the CNS. There are significant differences between the two regions, including their functions and composition.
The CNS is primarily responsible for processing and coordinating most of the
functions of the human body. The brain consists mainly of nervous tissue, with about 100 billion nerve cells, and can be thought of as the control center of all both voluntary and involuntary human actions. The brain is directly connected with the spinal cord, which enables the brain to communicate with other parts of the body.
The CNS has basically two kinds of nervous tissue: grey matter and white matter.
Grey matter consists of the unmyelinated parts of neurons including cell bodies, dendrites, axon terminals and some unmyelinated axons. White matter is almost completely made of axons, the color arising from the thick myelin layers. As such, both white and grey matter have different roles in the central nervous system.
The PNS consists of all the parts of the nervous system that connect to the CNS.
It is made up primarily of nerves – enclosed bundles of axons coupled with blood vessels and protective tissue. Nerves can be categorized according to their origin or destination. Cranial and spinal nerves act as links between the CNS and the rest of the body and are in charge of performing sensory and motor functions of the body. The sensory division carries signals beginning from the internal or external environments of the body to the CNS. Such signals may come externally from sight, touch or hearing, or internally from the feel of hunger or tiredness. Conversely, the motor division transmits signals coming from the CNS to the muscles, essentially generating a reply to previously received signals.
A more general way to divide the PNS is to decompose it to the somatic and au- tonomic nervous system. The somatic nervous system comprises the sensory and motor divisions excluding the autonomic parts. It is the consciously controlled part of the PNS responsible for the conduction of nerve impulses to skeletal muscles, thus enabling interaction with the external environment. The autonomic nervous system, on the other hand, is responsible for the subconscious or involuntary im- pulses such as blood flow or breathing. The autonomic nervous system itself can be divided into two categories: the sympathetic and parasympathetic nervous systems that essentially work in opposite fashion to each other. The sympathetic division is activated during situations of high stress, basically preparing the body for emer- gency action. It is responsible for increasing heart rate, releasing adrenaline or other stress hormones, and increasing sweating. The parasympathetic division acts as its counterpart, trying to inhibit its effects by decreasing heart rate, conserving energy and generating other calming effects. The bodily state of a person is essentially the balance between these divisions.