UCLA

Amyloid inclusions—typical of synucleinopathies such as Alzheimer’s and Parkinson’s disease—have been identified for the past two decades within the brains of infants and young children afflicted by lysosomal storage diseases. Lysosomal storage diseases are a family of seventy rare monogenic disorders, many of which involve nonfunctional mutations in enzymes pertaining to lysosomal degradation pathways. A sizable proportion of these cases presenting amyloid inclusions have involved lysosomal storage diseases characterized by aberrant sphingolipid metabolism, in which specific sphingolipids accumulate due to particular hydrolases being rendered nonfunctional. These findings strengthen the emerging relationship between early-onset lysosomal storage diseases and late-onset neurodegenerative diseases initially established by the identification of lysosomal storage disease-implicated genes as risk factors that lead to a more severe and earlier onset form of Parkinson’s disease. More generally, these lysosome-related genetic risk factors point to a link between metabolic dysfunction and proteopathic aggregation that has implications for not only these rare diseases but also prevalent neurodegenerative diseases as well. Here, I review what is currently understood about the role of the lysosome within alpha-synuclein pathology setting up the presentation of my thesis research: an investigation of how disease-implicated lipids may directly contribute to the pathogenesis of a-syn inclusions. With Thioflavin-T fluorescence kinetic assays and negative-stain electron microscopy, I found that psychosine, glucopsychosine, and sphingosine greatly reduce the lag phase---representative of amyloid nucleation---of recombinant alpha-synuclein aggregation in vitro when compared to other disease-implicated lipids. My experimental findings prove that the effect of these sphingolipids is specific and not solely due to molecular crowding. Together with recent literature findings, these results suggest that the primary amine group of these three lipids of interest influences the propensity of alpha-synuclein to form fibrils. The kinetic evidence put forth by this research serves as a foundation on which further studies can be built to understand the consequences of these lipids on the resulting structural and functional properties of the proteopathic aggregates within their relevant disease contexts. This will ultimately support future therapeutic intervention strategies for neurodegenerative diseases that span the age spectrum.