Plenary Lecture by Greg Petsko. Biennial Meeting of the British Biophysical Society, Liverpool, 8 July 2016.
Retromer is a multi-protein complex that traffics endosomal cargo back to the Golgi and to the plasma membrane. It also plays a vital role in lysosomal maturation and homeostasis. Implicated by human genetics in both sporadic and familial Alzheimer’s disease (AD), and more recently in familial Parkinson’s disease (PD), retromer has been shown to traffic the Amyloid Precursor Protein (APP) away from the endosome, where the beta-secretase is optimally active, thereby regulating Aβ peptide accumulation. The complex has also been implicated in the trafficking of alpha-synuclein. We have identified pharmacological chaperones that enhance retromer stability and function, with the goal of redirecting APP away from those compartments in which it is proteolyzed. First, we relied on biophysical measurements to identify the ‘weak link’ of the complex, and to complete an in silico screen of small molecules predicted to enhance retromer stability. Among the hits, an in vitro assay identified one molecule that stabilized retromer against thermal denaturation by more than 10 degrees C. Second, we turned to cultured hippocampal neurons, showing that the small molecule increases the levels of retromer proteins, shifts APP away from the endosome, and decreases Aβ accumulation dramatically, in a dose-dependent manner. Similar studies have also shown that increase in retromer function rescues several different models of Parkinson’s disease. Together, these findings clarify mechanisms of retromer stability, and identify a strategy that has therapeutic potential for AD and possibly also for other neurodegenerative disorders.
