New drug targets for neurodegeneration
NDs such as Alzheimer's disease (AD) and Parkinson's disease (PD) share common pathologies that could be resolved by regulating PREP levels. Eight academic institutes and three small and medium-sized enterprises (SMEs) joined forces in the NEUROPRO project to provide necessary expertise for translating research into commercial technology for clinical application. During this four-year project, significant results were achieved. Several techniques such as immunofluorescence double labelling, confocal laser scanning microscopy and peptidomics helped understand PREP function and interaction with other proteins and cytoskeletal components. Researchers demonstrated that modifying PREP levels to prevent learning and memory losses will not work as several key processes are compromised in neurodegeneration and neuroinflammation. PREPs were linked with intracrine and endocrine processes, intracellular processes like signalling and secretion, as well as with extracellular processes like neural plasticity. Structural analysis of PREP, PREP inhibition and peptidomics provided novel drugs for ND therapy by PREP inhibition using Z-Pro-Prolinal (ZPP) or KYP-2047. Cellular models revealed that PREP is critical in processing amyloid precursor protein (APP). AD could be caused due to dysfunctional APP metabolism or clearance as well as abnormal changes in PREP interaction with tau proteins. PREPs modified alpha-synuclein aggregation patterns that cause plaque deposition associated with neuro-degeneration. This was demonstrated clearly in animal and cellular models of PD and administering PREP inhibitors substantially reduced alpha-synuclein plaque density. Results were supported by PREP and alpha-synuclein co-localisation seen in actual PD brains. A novel peptide chip technology for peptide microarray analysis was validated for diagnostic and clinical research applications. PREP expression level variation in human serum makes it a reliable marker for multiple sclerosis (MS) and hepatic encephalopathy. PREP levels could also be used for disease prognosis and treatment monitoring in NDs. Hypotonia–cystinuria syndrome (HCS) causes neonatal hypotonia and dwarfism due to congenital PREP-like (PREPL) deficiency. NEUROPRO scientists provided novel insight into PREPL structure, function and interaction with cytoskeletal proteins to reveal the pathophysiology of HCS. AD brain analysis showed that the dimer–monomer equilibrium of PREPL proteins were more monomeric in AD brains. Research results will be invaluable in designing therapeutic regimens for patients enrolled in clinical trials. Research outcomes were disseminated via conferences, in over 40 publications in scientific peer-reviewed journals, through the Web of KnowledgeSM database, and at national and international scientific meetings as well as on the project website. Project discoveries could lead to five patent applications for clinical use in NDs like AD and PD, MS, HCS and neuroinflammation.
