Abstract

With the aging of society, neurological disorders such as Parkinsonism are causing serious socio-economic problems as there are, at present, only therapies that treat the symptoms. The disordered alpha-synuclein (SYN) and Tubulin Polymerization Promoting Protein (TPPP), which are expressed in neurons and oligodendrocytes of normal human brain, respectively, are hallmarks of these diseases. These hallmarks are co-enriched and co-localized in both cell types leading to the development of Parkinson’s disease (PD) and multiple system atrophy (MSA). These ‘chameleon’ proteins display both physiological and pathological functions, thus neither of them is an ideal drug target.  The Parkinsonism research has been focusing predominantly on the elimination of the pathological assembly of SYN, the fatal species in the development of these diseases. Accordingly, the therapeutic methods suggested so far include depletion of the accumulated SYN by miRNAs or siRNAs or by using PROTAC technology, which can affect the pathological aggregations. Our innovative strategy denoted “interface drug targeting” consider the TPPP-promoted SYN aggregation and identified the segments of both proteins involved in the pathological hetero-association. The flexible core region (147-156 aa) of TPPP s and the C-terminal segment of SYN (126-140 aa) have been identified as potential interacting binding regions, the deletion of which abolishes the hetero-association. In addition, the SYN fragment inhibited the pathological assembly of the two hallmark proteins as visualized in living human cells by immunofluorescence confocal microscopy. Our data have revealed that although targeting chameleon proteins is a challenging task; nevertheless, the validation of a drug target can be achieved by identifying the interface of the complexes of the partner proteins existing at the given pathological conditions. The “interface-targeting strategy” for Parkinsonism does impede the pathological TPPP-induced SYN aggregation; in addition, it ensures the recovery of the physiological functions of both multifunctional proteins. Based on these recent findings, we suggest that the clinical PD/MSA research focuses on the neglected role of TPPP occurring exclusively at pathological conditions to promote the cure of Parkinsonism.