The Aggregation Inhibitor Peptide QBP1 as a Therapeutic Molecule for the Polyglutamine Neurodegenerative Diseases

Misfolding and abnormal aggregation of proteins in the brain are implicated in the pathogenesis of various neurodegenerative diseases including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases. In the polyQ diseases, an abnormally expanded polyQ stretch triggers misfolding and aggregation of the disease-causing proteins, eventually resulting in neurodegeneration. In this paper, we introduce our therapeutic strategy against the polyQ diseases using polyQ binding peptide 1 (QBP1), a peptide that we identified by phage display screening. We showed that QBP1 specifically binds to the expanded polyQ stretch and inhibits its misfolding and aggregation, resulting in suppression of neurodegeneration in cell culture and animal models of the polyQ diseases. We further demonstrated the potential of protein transduction domains (PTDs) for in vivo delivery of QBP1. We hope that in the near future, chemical analogues of aggregation inhibitor peptides including QBP1 will be developed against protein misfolding-associated neurodegenerative diseases. 1. Introduction Neurodegenerative diseases are a group of disorders, which are caused by progressive degeneration of neurons in various areas of the brain specific for each disorder, resulting in various neurological and psychiatric symptoms corresponding to each affected brain area. Few effective therapies have been established to date for these diseases, largely due to the fact that the underlying cause of the neurodegeneration long remained unknown. However, accumulating evidence now indicates that many of these neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), the polyglutamine (polyQ) diseases, amyotrophic lateral sclerosis, and the prion diseases, share a common pathomechanism (Figure 1). Pathological and biochemical studies have revealed that various protein inclusions accumulate inside and outside of neurons in the diseased brains, such as senile plaques composed of amyloid-β and neurofibrillary tangles composed of tau in AD, and Lewy bodies composed of α-synuclein in PD. Although the significance of these protein inclusions on disease pathology long remained controversial, recent molecular genetics studies revealed that the mutations responsible for the inherited forms of these diseases render the proteins to be prone to misfold and aggregate, or lead to the overproduction of aggregation-prone proteins. Furthermore, not only such genetic mutations, but also multiple environmental factors are thought to trigger the misfolding of otherwise normal proteins, and