The Twofold Role of Osteogenic Small Molecules in Parkinson's Disease Therapeutics: Crosstalk of Osteogenesis and Neurogenesis

Abstract

Deemed one of the most problematic neurodegenerative diseases in the elderly population, Parkinson's disease remains incurable to date. Ongoing diagnostic studies, however, have revealed that a large number of small molecule drugs that trigger the BMP2-Smad signaling pathway with an osteogenic nature may be effective in Parkinson's disease treatment. Although BMP2 and Smad1, 3, and 5 biomolecules promote neurite outgrowth and neuroprotection in dopaminergic cells as well, small molecules are quicker at crossing the BBB and reaching the damaged dopaminergic neurons located in the substantia nigra due to a molecular weight less than 500 Da. It is worth noting that osteogenic small molecules that inhibit Smurf1 phosphorylation do not offer therapeutic opportunities for Parkinson's disease; whereas, osteogenic small molecules that trigger Smad1, 3, and 5 phosphorylation may have strong therapeutic implications in Parkinson's disease by increasing the survival rate of dopaminergic cells and neuritogenesis. Notably, from a different perspective, it might be said that osteogenic small molecules can possibly put forth therapeutic options for Parkinson's disease by improving neuritogenesis and cell survival.

Figure 1

Schematic representation of crosstalk between dopaminergic neurons and osteoblasts induced by small molecules involved in the Smurf1 signaling pathway is shown. (a) This picture highlights the effect of Smurf1 mimicking small molecules in neurogenesis. Induction of p-Smurf1 led to RhoA ubiquitination and resulted in less ubiquitinated Par6 in a competitive manner. This cascade along with cdc42 and Rac1-induced neurite outgrowth. However, RhoA, through the activation of Rho-associated protein kinases (ROCKs), phosphorylates myosin light chain (MLC) and LIMK, both of which separately phosphorylate cofilin. p-cofilin depolymerized actin and inhibited neuriotogenesis. In addition, GDNF, through an increase in Six2, degrades the P53 protein and induces Bcl2 overexpression, which leads to cell viability improvement. (b) This picture highlights the effect of Smurf1 mimicking small molecules in the inhibition of osteogenesis. Induction of Smurf1 and subsequent Smurf1 phosphorylation led to Runx2 degradation and osteogenesis inhibition.

Figure 2

A schematic representation of the crosstalk between dopaminergic neurons and osteoblasts induced by small molecules involved in the Smad signaling pathway is shown. (a) This picture highlights the effect of Smad1/3/5 mimicking small molecules in neurogenesis and apoptosis inhibition. Induction of Smad 1/5 triggers a cascade that leads to the interaction of Smad4 as a co-Smad with p-Smad 1/5 and translocation of the complex into the nucleus and neurites. Small molecules mimicking Smad 3 resulted in the formation of the Smad4-p-Smad3 complex and its translocation into the nucleus and inhibition of neural apoptosis. (b) This picture highlights the effect of Smad1/3/5 mimicking small molecules in osteogenesis and apoptosis inhibition. The previously mentioned cascade in dopaminergic neurons occurs in osteoblasts. Smad1/5 mimicking small molecules triggers the cascade that leads to osteogenesis, while Smad3 mimicking small molecules triggers the cascade that leads to apoptosis inhibition in osteoblasts.

Figure 3

(a) Smad MH2 domain bound to DNA (PDB: 1MHD). (b) PY motif in the linker region of Smad1 bound to the WW domain of Smurf1. The small molecule that occupies this pocket of the binding site inhibits Smad1 ubiquitination (PDB: 2LAZ).

Figure 4

Common small molecules between neurogenesis and osteogenesis that function by focusing on the Smad signaling pathway. Drawn by Pathway Studio.