Investigating the molecular pathogenesis of cognitive decline in Parkinson's disease

Baylor College Of Medicine, Houston TX

Investigators

Abstract

Parkinson?s disease affects more than 10 million patients worldwide, representing a massive global health problem. In addition to motor symptoms, many Parkinson?s patients suffer from cognitive decline in later disease stages, with the majority of patients living with Parkinson?s for 10 years developing cognitive symptoms. Given that the population is living longer than ever before, the number of Parkinson?s patients suffering from cognitive symptoms will continue to rise in coming years. Although some progress has been made in developing therapies to alleviate motor symptoms in Parkinson?s patients, the biological basis of cognitive decline is poorly understood, with no known therapies in development. Elucidating the mechanisms and key players underlying cognitive decline in Parkinson?s disease is thus urgently needed to guide rational therapeutic development. Human clinical and genetic evidence converge on dysfunction and aggregation of the protein ?-Synuclein as a key initiator of neurotoxicity underlying motor symptoms in Parkinson?s disease; however, how ?-Synuclein leads to cognitive symptoms remains poorly understood. Recent clinical studies have identified pathological aggregates of Tau, a protein linked to dementias including Alzheimer?s, present in the brains of Parkinson?s patients suffering from late stage cognitive decline. Given the known roles of Tau in causing cognitive impairment, these findings bright to light a possible disease cascade in which ?-Synuclein dysfunction induces Tau pathology, marking a transition from motor symptoms to cognitive impairment. While supported by clinical evidence, this model has never been formally tested in a controlled experimental setting that allows for spatiotemporal resolution of ?-Synuclein and Tau pathology development over time to determine their respective roles to motor and cognitive demise. This project aims to delineate the relative contributions of ?-Synuclein and Tau to distinct Parkinson?s symptoms by developing novel mouse models that carry knock-in of ?-Synuclein pathogenic mutations and variants (E46K missense mutation, Y39E phospho-mimetic, or SNCA triplication) as a disease trigger. By knock-in of pathogenic variants to the endogenous mouse ?-Synuclein coding sequence, the native cell- and tissue-type specific expression will be maintained, providing a physiologically relevant animal model to study the pathogenic effects of ?-Synuclein. To further provide the human disease-relevant context, ?-Synuclein knock-in mice will be analyzed on a humanized Tau background to allow the induction of Tau pathology by ?-Synuclein to occur. The appearance of ?-Synuclein and Tau pathologies in distinct brain areas will be tracked over time and correlated to the resulting motor and cognitive deficits to determine their respective roles in disease progression. Further, the mechanism by which ?-Synuclein induces Tau pathology will be explored by profiling of post-transcriptional and post-translational modifications of Tau induced by ?-Synuclein, followed by systematic screening to identify the specific molecule that mediates this process. This project will reveal novel insight into the molecular pathogenesis underlying cognitive decline in Parkinson?s disease in an effort to open new therapeutic avenues.