Role of Mitochondrial Heat-shock Proteins and Immunophilins in Neuro Degenerative Diseases

Abstract

Abstract:: Pathophysiologic conditions of neurodegenerative diseases are unquestionably related to protein misfolding. The accumulation of misfolded proteins into relatively ordered structures such as fibrillar intracellular and extracellular amyloids results in tissue lesions that lead to neuronal loss and brain damage. In these pathologies, the occurrence of protein aggregates suggests certain inefficient or insufficient cellular response of those molecular chaperones that should properly assist the folding of the client proteins. In this regard, all the experimental models for neurodegenerative diseases have demonstrated that the overexpression of molecular chaperones provide effective neuroprotection. A subset of these molecular chaperones corresponds to a group of proteins that exhibit peptidylprolyl isomerase enzymatic activity, the immunophilins. Most of the family members of the latter group were first described as responsible of the immunosuppressive response or they were reported as members of the chaperone complex associated with HSP90 in steroid receptor oligomers. In this article we review some aspects of the liaison between molecular chaperones and neurodegenerative diseases, in particular heat-shock proteins and immunophilins with demonstrated influence in the proper function of mitochondria. This article is intended to address a field that represents a yet critical unmet clinical need for the development of neuroprotective molecules focused on potentially novel molecular targets.

In Silico Study of the Interactions of Anle138b Isomer, an Inhibitor of Amyloid Aggregation, with Partner Proteins

“…The organization of such proteins into relatively ordered structures, such as fibrillar intracellular and extracellular amyloids, leads to tissue and brain damage. In these pathologies, the appearance of protein aggregates indicates inefficient cellular reactions involving molecular chaperones that contribute to the correct folding of partner proteins [30]. This study aimed to expand our understanding of the possible mechanisms of interaction of the Anle138b isomer ligand, which is promising for clinical use and prevents the aggregation of cellular amyloidogenic proteins.…”

“…CypA is involved in basic neuronal functions, such as axonal transport and synaptic vesicle assembly; however, its most interesting role is neuroprotection. CypA prevents protein aggregation and binds unstructured or irregularly organized proteins [30]. As mentioned before, AαSyn is an unstructured protein, and its cellular partners can be different proteins and ligands.…”

“…In cells, AαSyn molecules form complexes with CypA [29,30]. CypA belongs to the family of immunophilins or chaperones containing the peptidyl prolyl cis/trans isomerase domain (PPIase).…”