VCP Project

A common mechanism in several neurodegenerative diseases (NDD) is the abnormal accumulation of misfolded aggregated proteins forming intracellular inclusions or extracellular aggregates in specific areas of the brain. For example, Alzheimer’s disease (AD) is characterized by extra-neuronal aggregation of Aß amyloid peptides forming the amyloid plaques and intra-neuronal accumulation and aggregation of abnormally modified microtubule-associated Tau proteins forming the so-called neurofibrillary tangles. 

Misfolded proteins generated in various cellular compartments are efficiently cleared by protein quality control and clearance systems. However, these systems are inefficient or impaired in several NDD leading to abnormal accumulation of disease-specific proteins. Therefore, strategies aiming at promoting the clearance of these aggregates and restoring protein homeostasis in NDD would be of therapeutic value.

VCP (Valosin Containing Protein) is a key player in protein quality control and clearance. The dysfunction of this type II AAA ATPase is associated to NDD including, inclusion body myopathy with Paget’s disease and frontotemporal dementia (IBMPFD) and amyotrophic lateral sclerosis. Therefore, VCP constitutes a potential pharmacological target for the treatment of NDD.


 

Figure 1: Role of VCP in protein quality control and clearance (Franz A et al. Biochim. Biophys. Acta. 2014, 1843, 205-215).

 

As part of our collaborative project targeting AD pathophysiology, involving chemists and neurobiologists of UMR-S 1172 research group, several compounds named MSBD have been developed and lead compound is currently ending clinical phase I. MSBD act on both amyloid and Tau pathologies and were shown to improve cognitive deficits in transgenic mice models.

Investigation of their molecular target led to the identification of VCP. Our current data suggest that MSBD repress the production of Aβ and promote Tau proteolysis, both in vitro and in vivo, through a VCP-dependent mechanism. However, the mechanism remains to be unraveled. Therefore, the main question we have to address is how MSBD modify the activity of this AAA-ATPase and consequently modulate both the amyloid and tau pathology.

Figure 2: Cryo-EM structure of human VCP bound to ADP (PDB code: 5FTK) 2014.