Investigating Glial Contributions During Parkinson’s Disease Pathogenesis Using Patient-Specific iPSC-Derived Cells

摘要: Parkinson’s disease (PD) is associated with the degeneration of ventral midbrain dopaminergic (vmDA) neurons and accumulation cytoplasmic inclusions, known as Lewy Bodies, composed mainly aggregated α synuclein in surviving vmDA neurons. This process, along underlying cell-autonomous pathogenic mechanisms, has been successfully modeled using patient-specific induced pluripotent stem cell (iPSC) technology. Non-cell autonomous neurodegeneration during PD suggested by past observational studies, but remains to be experimentally tested. Here, we generated astrocytes from iPSC lines derived familial patients G2019S mutation on Leucine rich repeat kinase 2 (LRRK2) gene, Sporadic patients, well healthy age-matched individuals (to whom will refer wild type (WT)). To assess possible non-cell role pathogenesis, a co-culture system was devised between iPSC-derived vmDAn potential neuron-glia crosstalk. WT displayed morphological signs (such few short neurites, beaded-like necklace neurites) abnormal, astrocyte-derived, when co-cultured top LRRK2-PD astrocytes. Upon further investigation, alone phenotypes reminiscent those observed PD-iPSC-derived vmDAn, including alterations autophagy mitochondrial dynamics, progressive synuclein, compared A CMA activator drug, QX77.1, rescued dysfunction consequence cleared previously accumulated α-synucein Conversely, partially prevented appearance diseaserelated neurodegeneration. neuroprotective appears managed via activation glia reactive state, suggests have an impaired relation neuroprotection reactivity, which results neurodamaging effects. Our findings unveil crucial contribution open path exploring novel therapeutic strategies aimed at blocking cross-talk glial cells. Words: 318