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On the basis of the previously proposed hierarchic organisation of the central nervous system (CNS) and of its syntropic behaviour, a view of neurodegenerative diseases focusing on the assemblage of abnormal multimeric proteins (pathologic protein mosaics (PMs)) is proposed. Thus, the main focus of the present paper is on Parkinson's disease (PD) as a neurodegenerative disease, which has as crucial feature protein conformational alterations and formation of pathological PMs. Two interconnected cellular dysfunctions are discussed as main pathogenic factors of PD syndromes, namely mitochondrial deficits (i.e. energy failure, especially critical for Substantia Nigra DA neurons) and conformational protein alterations (due to genetic or environmental causes). Conformational protein alterations can trigger pathological phenomena via the loss and/or the gain of new functions. In particular, altered proteins can lead to the formation of abnormal PMs, which can, inter alia, cause distortion of cellular structures, toxic functions and/or formation of improper membrane ion channels. In view of the fact that disordered proteins can easily acquire unwanted conformation, the "disorder index" (DI) for proteins involved in PD has been evaluated. It has been found that both alpha-synuclein and tau-protein have high DI. This datum is in agreement with the observation that these two proteins synergistically promote polymerisation of each other into amyloid fibrils, favouring the formation of Lewy bodies.

Biological systems are organized in intricate and highly structured networks with hierarchies and multiple scales. Cells can be considered as “meso-scale level” systems placed between the “macro-scale level ” (systems of cellular networks) and the “micro-scale level” (systems of molecular networks). In fact, cells represent complex biochemical machineries made by networks of molecules connected by biochemical reactions. Thus, the brain should be studied as a system of “networks of networks”. Recently, the existence of a Global Molecular Network (GMN) enmeshing the entire CNS was proposed. This proposal is based on the evidence that the extra-cellular matrix is a dynamic molecular structure capable of storing and releasing signals and of interacting with receptors and proteins on the cell membranes. Proteins have a special role in molecular networks since they can be assembled into high-order molecular complexes, which have been defined as Protein Mosaics (PM). Protein monomers in a PM (the “tesserae” of the mosaic) can interact via classical and non-classical cooperativity behaviour involving allosteric interactions. In the present paper, new features of allostery and cooperativity for protein folding, assemblage and topological features of PM will be discussed. Against this background, alterations in PM via allosteric modulations and non-classical cooperativity mechanisms may lead to protein aggregates like beta amyloid fibrils. Such aggregates cause pathological changes in the GMN structure and function leading to neurodegenerative diseases such as Alzheimers disease. Thus, a novel view of the so called Protein Conformational Diseases (PCD) is proposed.

Proteins are endowed with the "Lego property", i.e., the capability of steric fitting with other proteins to form high molecular weight complexes with emergent functions. These interactions may occur both as horizontal molecular networks at the plasma membrane level and as vertical molecular networks, i.e., towards the extra- and/or intracellular side of the cell. The present paper broadens this view by proposing the existence of three dimensional molecular networks, mainly made by proteins and carbohydrates, which might interact with each other at boundaries of compartments such as plasma membranes to form a "global molecular network" (GMN) that pervades the intra- as well as the extra-cellular environment of the entire central nervous system. The GMN is a potentially plastic structure regulated through several means. For example, its extra-cellular part is under the remodeling action of the matrix metalloproteinases. The proposal of a GMN has physiological and pathological implications. In primis, classical synaptic transmission, gap junctions and volume transmission signals by modulating GMN could importantly contribute to the "binding phenomenon", i.e. the phase synchronization of firing rates in far-located neuronal cortical groups. Secondly, alterations in protein conformation could alter the GMN organization and hence the neuronal network morphology and function. This could lead to the formation of abnormal protein aggregates such as amyloid plaques and neurofibrillary tangles, which, in turn, might affect the GMN function and/or the reciprocal interactions between its parts especially at the boundaries between compartments.