Entropy-driven, temperature-responsive, aggregations of cells and macromolecules: erythrocytes and α-synucleins as exemplars

The biophysics of the homoaggregation of cells (erythrocyte rouleaux) share many features of the homoaggregation of macromolecules such as α-synuclein. Consistent with a role for temperature-dependent entropic forces, evidence from both homoaggregations suggests that aggregation pressures could be determined extrinsically, rather than solely intrinsically by the concentration of a macromolecule. Critical here are concentrations of members of the local macromolecule collective and binding of water. Over evolutionary time certain self-proteins, especially the intrinsically disordered, have been under positive selection pressures (i.e., are conserved), seemingly to avoid misinteractions. For organisms with high expression of the corresponding genes, these misinteractions might have been harmful had they led to homoaggregations of the proteins. The conservation (i.e., a slowing of evolutionary rates due to functional constraints), which correlates with high expression levels (the "ER anticorrelation"), has long puzzled geneticists. Supported by recent developments, historical studies (Fåhraeus, Muller, Lauffer) from a wide range of disciplines offer promising solutions to this and other problems. The resulting knowledge integrations cast fresh light on the changes from monomeric to polymeric forms that are deemed to play fundamental roles in intracellular mechanisms for discrimination between self-macromolecules and those derived from invading microorganisms. However, these aggregates may also initiate various neurological diseases. Lifestyle changes that prevent transient increases in body temperature might diminish the diseases without unduly harming the immunological defenses that rely on heat-shock proteins.