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There is increasing evidence that unfolded and misfolded proteins initiate a cascade of pathogenic protein-protein interactions that culminate in neuronal dysfunction. This is a multistep process which results in toxic protein aggregates; thus they are potent targets for development of early diagnosis and of drugs to improve therapies of conformational diseases. The hallmark proteins of these diseases such as Parkinson’s, Alzheimer’s or Huntington’s diseases, are α-synuclein, tau or mutant huntingtin, respectively, which do not have well-defined 3D structures and require protein partners to express their pathological functions. In this paper we review a new unstructured protein denoted Tubulin Polymerization Promoting Protein, TPPP/p25, from the discovery to its enrichment in human pathological inclusions characteristic for synucleinopathies with specific emphasis on its pursuits in single cells. There is a gappy area in the research of unfolded proteins referring to their structure-derived physiological and pathological functions. The studies of TPPP-homologous proteins at different levels of organization, molecular, cellular and tissue levels, rendered possible to reveal some TPPP/p25 specific structural and functional features, in addition to the general items for the role of the unfolded regions of the highly flexible proteins in their physiological and/or pathological functions.

The term cell architecture refers to the fine structure of living cells, including their dynamically organized structures. New techniques and research strategies have been developed to characterize the structures and functions of the cytomatrix and their relationships in various cell types. The resulting in vitro and in vivo data have provided evidence that the cytoskeletal network is complex, characterized not only by tightly bound microtubule-associated proteins, but also by so-called cytosolic enzymes involved in different metabolic processes. The latter are not necessarily distributed homogeneously within the interstitial void, but transiently associate to the skeleton or form enzyme clusters (as described for example in Chapters 23-24 in this book). The heteroassociations of macromolecules are enhanced by crowding effects (Minton & Wilf, 1981), however, with a specificity, crucial from the physiological point of view, that is based on surface complementarity. These transient interactions are stabilized by weak interacting forces, and could be changed by changing ionic strength, pH or concentrations of endogenous effectors (e.g. metabolites and other proteins) or exogenous agents (e.g. drugs and pollutants). Consequently one would expect that the sensitivity of these complex structures towards effectors might depend on the organization state of macromolecules. A cellular network of structural proteins could function as an organizing centre for metabolic enzymes and could create appropriate conditions for formation of intermediates. Enzyme clusters of sequential enzymes of a metabolic pathway can provide kinetic advantages for metabolism such as channelling complexes. The physiological significance of the formation of these channelling complexes may vary from system to system, but in several cases their physiological relevance is not yet well understood (for more discussion, see Ovadi, 1991, and other articles in the same issue of the journal.