Galectins proteins (proteins that bind sugar molecules) mediate the cellular response to endocytic (transfer of molecules to cells) vesicles (storage sacks) ruptured by amyloid proteins (protein clumps), such as alpha-synuclein (sticky protein that accumulates in the brains of those with Parkinson's). We have observed that vesicles containing alpha-synuclein either fuse with similar vesicles into larger enclosures within the cell or are transferred to neighboring cells. Continued fusion of these vesicles may lead to the formation of Lewy bodies (bundles of alpha-synuclein proteins), which is supported by the observation that Lewy bodies from individuals with Parkinson's disease (PD) are surrounded by a halo of galectin proteins; however, release of these vesicles may promote the propagation (spread) of alpha-synuclein pathology. This study aims to define the role of galectin proteins in these distinct outcomes.
Vesicle rupture by alpha-synuclein causes autophagic (regulated destruction of cellular materials) stress in cells, which in turn drives the secretion of alpha-synuclein, thereby driving the cell-to-cell propagation of alpha-synuclein in PD.
We will reduce the amount of specific galectin proteins and other cellular factors that mediate recruitment of autophagic machinery to ruptured vesicles in primary dopamine cells derived from induced pluripotent stem cells (cells that can give rise to any types of cells in the human body). We will monitor the degree to which reducing these cellular factors impacts the release of alpha-synuclein. We will also examine tissue from those with PD who received therapeutic neuronal grafts (transplanted tissue) to determine the degree to which galectin proteins are present in Lewy bodies.
Impact on Diagnosis/Treatment of Parkinson's disease:
Understanding the cellular mechanisms underlying Lewy body formation and cell-to-cell propagation of alpha-synuclein pathology may provide therapeutic opportunities to slow the progressive nature of PD.
Next Steps for Development:
Cellular factors identified as driving Lewy body formation or cell-to-cell transfer of alpha-synuclein will be examined in pre-clinical models, with the ultimate goal of targeting these proteins to slow disease progression in PD.
Secretory autophagy is a process in which cells dispose of unwanted proteins they can't digest. These unwanted proteins are packages in small sacks called vesicles inside the cell in preparation for disposal. We have found that dopamine-producing brain cells use secretory autophagy to dispose of alpha-synuclein, a sticky protein that clumps in the brains of people with Parkinson's disease (PD). Vesicles with alpha-synuclein can stick together inside the cell, creating clumps called Lewy bodies, which have been linked to neurodegeneration. Alternatively, vesicles with alpha-synuclein leave the cell and enter cells located nearby, thus spreading the abnormal alpha-synuclein. Firstly, proteins that enable secretory autophagy may be potential targets for therapies that reduce the abnormal spread of alpha-synuclein from cell to cell in the brain. One of such proteins we identified is galectin 3. Secondly, we studied brain samples donated by people after death. People who donated these samples received brain cell transplant before death. We noticed that Lewy bodies in transplanted cells differed from those in the brains of people with untreated Parkinson's. This means that Lewy bodies grow gradually. We aim to define stages of Lewy bodies growth by studying such brain samples. This may help us understand when Lewy bodies begin to grow in the brains of people with PD, which may improve our understanding of disease mechanism and progression.