Biology subjects

LeeBae, J.

Publications and source records attributed to LeeBae, J..

2 recordsLinked to original sources

bioRxiv2025

Molecular aging is the main driver of Parkinson's Disease

Aging as well as the presence of -synuclein (-syn) oligomers in the brain are indisputably linked to Parkinsons disease (PD). A central concept of geroscience is that the biological processes of aging drive the onset of aging-associated diseases. The extent to which the biological processes of aging directly contribute to PD and the inter-relationship with -syn oligomers for the onset of PD symptoms remains unclear. Using an inducible -syn oligomer mouse model of PD, we demonstrate that the induction of PD associated -syn oligomers for the same timespan caused PD associated symptoms only in aged, but not in young mice. Biochemical studies revealed that -syn oligomer formation precedes motor decline in these aged mice, and age together with -syn expression determine the motor phenotype. Single-nucleus RNA sequencing (snRNA-seq) identified a PD disease signature that was particularly linked to basal ganglia neurons (BGNs) and was in part shared with an aging transcriptional signature. PD symptoms, as well as the PD Signature, were significantly altered by a short-term pharmacological attenuation of the activity of the small RhoGTPase CDC42 in already aged animals with PD symptoms. Attenuation of activity of CDC42 is known to target the general biological processes of aging. Interestingly, the intervention did not affect the amount of -syn oligomers in the animals, while still improving phenotypes. Together, the data demonstrates that the biological processes of aging are a major causative driver for the onset of PD in the -syn model of PD.

neuroscience↗

bioRxiv2025

Spreading alpha-Synuclein Oligomers Trigger Astrocyte Reactivity and Astrocyte-glutamatergic Neuron system dysfunction in an Age-Dependent Manner

BackgroundParkinsons disease (PD) is characterized by the progressive accumulation and spatio-temporal spread of -synuclein (-syn) oligomers and a progressive loss of dopaminergic neurons. Many studies showed a direct cytotoxic effect of -syn oligomers on neurons. Other cell types including astrocytes were also reported to show specific responses to -syn and are believed to play a role in the spreading of PD pathology. MethodsTo investigate the transcriptional and cellular consequences of -syn oligomer spreading, we employed spatial transcriptomics and single-nucleus RNA sequencing (snRNA-seq) in a transgenic PD mouse model expressing human -syn in neurons. We further compared our findings to published public snRNA-seq datasets from human PD patients ResultsOur analysis identified -syn spreading mostly to the substantia nigra and defined a transcriptional "Spreading Signature" associated with -syn pathology. We found an age correlated increase in astrocytes, close interactions between astrocytes and -syn, and transcriptional dysregulation of the astrocyte-glutamatergic neuron axis. We further identified two subtypes of glutamatergic neurons that are vulnerable to astrocytic changes. Comparative analysis with human PD snRNA-seq data showed concordant transcriptional changes related to astrocytic dysfunctions and diminished neuronal signaling. ConclusionBased on our results, we propose a model of -syn oligomer spreading involving astrocytes, glutamatergic synapses, and a disturbance in the astrocyte-glutamatergic neuron axis.

neuroscience↗