Polymorphism in neurofilament protein assemblies induced by magnesium (II), calcium (II), and tannate ions

The squid giant axon has become well established as a model preparation for studies of the organization of the neurofilamentous network. A comprehensive model of this neurofilament structure as a three-dimensional supramolecular complex of fibrous proteins has been developed. The network pervades the axon and appears to have a functionally specific, intrinsic polymorphism taking the form of dense and less-dense, local, quasi-crystalline domains. The loss of this dynamic capacity for phase transition has been hypothesized as the underlying process through which abnormal configurations of neurofilaments arise, an example of which may be the paired helical filaments of Alzheimer's disease. An investigation was undertaken of neurofilament protein ultrastructure in a variety of experimentally produced ionic environments with the aim of defining in a systematic way general charge and concentration effects on assembly patterns.

Arrays of Paired Helical Filaments in Alzheimer's Disease

Massive formations of paired helical filaments (PHF) found in neurons and in neurites of senile plaques are a characteristic diagnostic feature of Alzheimer's disease. Factors which initiate the formation of these highly regular structures are not known. However, their helical symmetry displays a basic principle of organization of the neurofilamentous network which is common to all neurons whether normal or pathological. The configuration of PHF assemblies may also be determined by principles common to all types of helical filaments of the cytoskeleton.

ELECTRON MICROSCOPE AND EXPERIMENTAL INVESTIGATIONS OF THE NEUROFILAMENTOUS NETWORK IN DEITERS' NEURONS

The assembly of filamentous elements and their relations to the plasma membrane and to the nuclear pores have been studied in Deiters' neurons of rabbit brain. Electron microscopy of thin sections and of ectoplasm spread preparations have been integrated with physicochemical experiments and differential interference microscopy of freshly isolated cells. A neurofilamentous network extends as a continuous, three-dimensional, semilattice structure throughout the ectoplasm, the "plasma roads," and the perinuclear zone of the perikaryon. This space network consists of ∼90-Å wide neurofilaments arranged in fascicles which are interconnected by an exchange of neurofilaments. The neurofilaments consist of intercoiled ∼20-Å wide unit-filaments and are associated through cross-associating filaments with other neurofilaments of the fascicle and with microfilaments. The ∼20–50-Å wide microfilaments display intimate associations with the plasma membrane and with the nuclear pores. Electron microscopy of thin sections from glycerinated and heavy meromyosin-treated Deiters' neurons shows that actin-like filaments are present in the pre- and postsynaptic regions of synapses terminating on these neurons. It is proposed that the neurofilamentous space network serves a transducing function by linking plasma membrane activities with the genetic machinery of the neuron.