Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

Abstract

With the aging of population, neurological disorders, and especially disorders involving defects in protein conformation (also known as proteopathies) pose a serious socio‐economic problem. So far there is no effective treatment for most proteopathies, including Parkinson's disease (PD). The mechanism underlying PD pathogenesis is largely unknown, and the hallmark proteins, α‐synuclein (SYN) and tubulin polymerization promoting protein (TPPP/p25) are challenging drug targets. These proteins are intrinsically disordered with high conformational plasticity, and have diverse physiological and pathological functions. In the healthy brain, SYN and TPPP/p25 occur in neurons and oligodendrocytes, respectively; however, in PD and multiple system atrophy, they are co‐enriched and co‐localized in both cell types, thereby marking pathogenesis. Although large inclusions appear at a late disease stage, small, soluble assemblies of SYN promoted by TPPP/p25 are pathogenic. In the light of these issues, we established a new innovative strategy for the validation of a specific drug target based upon the identification of contact surfaces of the pathological SYN‐TPPP/p25 complex that may lead to the development of peptidomimetic foldamers suitable for pharmaceutical intervention.

A Potential Innovative Therapy for Parkinson’s Disease: Selective Destruction of the Pathological Assemblies of Alpha-Synuclein

“…SYN was the first identified causative gene of familial PD, all identified mutations can be found in the N-terminal region that affect the oligomerization, fibrillation and/or aggregation of SYN leading to the formation of the toxic species, see [1,5,6] and references therein. Until now, the following mutants have been identified to be involved in PD: A18T, A29S, A30P, E46K, H50Q, G51D, A53E and A53T [28] (Figure 1).…”

“…The unfolded SYN and TPPP/p25 are expressed distinctly in neurons [82,83] and OLGs [64,75], respectively, in healthy brain; however, they are co-enriched and co-localized in pathological inclusions in the cases of PD and MSA [84]. The interaction of SYN and TPPP/p25 has been proven at atomic, molecular and cellular levels as well as in post-mortem brain tissues [6,59]. Short peptide fragments have been produced by proteolytic degradation of the interacting proteins as well as by chemical synthesis based upon the interface segments identified experimentally using the wild type proteins [79,80].…”

“…One of the important factors in the PD research is related to the finding that SYN displays both physiological and pathological functions [5]; consequently, besides the specific and effective destruction of the accumulated SYN leading to the formation of its toxic assemblies/aggregations, the optimal SYN level has to be maintained/ensured for its physiological functions. In this chapter, the structural and functional potentials of SYN and Tubulin Polymerization Promoting Protein (TPPP/p25), hallmarks of PD [6], are reviewed leading to their molecular mechanism/pathomechanism in the initiation of PD and other synucleinopathies.…”

The 44th FEBS Congress in Krakow: celebrating the multidisciplinarity of biological research

“…We are, thus, delighted to present you with the successful outcome: 17 Review articles [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] and 2 Research articles [18,19] on topics as diverse as plant biology, evolutionary biology, chromatin, translation, the cytoskeleton, mitochondria and translational research.…”

“…On the translational side of things, you may find Review articles on mental disorders (Marta Wisniewska and colleagues, University of Warsaw, Poland) ; hypertrophic cardiomyopathy (Christoph Maack and colleagues, University Clinic Würzburg, Germany) ; drug targets in Parkinson's Disease (Judit Ovadi and colleagues, Hungarian Academy of Sciences, Hungary) ; and biomarker development in diabetes (Gordan Lauc and colleagues, University of Zagreb, Croatia) . Remarkably, Connie Jimenez (VU University, The Netherlands) and colleagues have contributed an interesting Perspective on the potential of urinary exosome proteomics in cancer biomarker development .…”