Spreading alpha-synuclein oligomers trigger astrocyte/microglial changes and astrocyte-glutamatergic neuron system dysfunction in an age-related manner
TL;DR
A model in which α-syn oligomer spreading, amplified by aging, simultaneously disrupts the astrocyte–glutamatergic neuron axis and drives microglia into a senescent DAM-like state is proposed, and candidate gene sets for both processes are provided for further investigation of glial dysfunction in PD.
Abstract
Parkinson’s disease (PD) is characterized by the progressive accumulation and spatio-temporal spread of α-synuclein (α-syn) oligomers and a progressive loss of dopaminergic neurons. Many studies showed a direct cytotoxic effect of α-syn oligomers on neurons. Other cell types including astrocytes or microglia were also reported to show specific responses to α-syn and are believed to play a role in the spreading of PD pathology. To investigate the transcriptional and cellular consequences of α-syn oligomer spreading, we employed spatial transcriptomics, single-nucleus RNA sequencing (snRNA-seq), and bulk RNA sequencing (bRNA) of isolated microglia in a transgenic PD mouse model expressing human α-syn in neurons. We further compared our findings to published public snRNA-seq datasets from human PD patients. Our analysis identified a transcriptional “Spreading Signature” associated with α-syn pathology in the substantia nigra in our PD mouse model. We found an age correlated increase in astrocytes, close interactions between astrocytes and α-syn, and transcriptional dysregulation of the astrocyte-glutamatergic neuron axis. We further identified two subtypes of glutamatergic neurons that are vulnerable to astrocytic changes. The surviving microglial population shifted towards a senescent, disease-associated microglia (DAM)-like state with enhanced phagocytic, lysosomal, and motile signatures, and the accumulation of swollen lysosomal pockets. Astrocytic and microglial changes, including diminished neuronal signaling, were partly concordant between mouse and human SN datasets. Based on our results, we propose a model in which α-syn oligomer spreading, amplified by aging, simultaneously disrupts the astrocyte–glutamatergic neuron axis and drives microglia into a senescent DAM-like state, and we provide candidate gene sets for both processes for further investigation of glial dysfunction in PD.