Macrophages in the dCLN are required for α-synuclein proteostasis in A53T PD model mice.

The metabolic disorder of α-synuclein in the central nervous system (CNS) is a key factor leading to excessive accumulation of aggregated α-synuclein and ultimately to the formation of Lewy bodies, which is one of the main pathological features of Parkinson's disease (PD). Although the mechanism underlying this process remains elusive, systemic metabolic abnormalities have been demonstrated to affect the progression of neurodegenerative diseases. The recent discovery of meningeal lymphatics provides a specific route for connection between the CNS and the periphery. As draining lymph nodes for CSF, the deep cervical lymph nodes (dCLN) are important for maintaining CNS homeostasis. However, whether and how macrophages in the peripheral dCLN system are involved in the α-synuclein homeostasis is largely unknown. Here, we report that macrophages in the deep cervical lymph node (dCLN) are required for maintaining α-synuclein proteostasis in an LRRK2 and lysosome-dependent pathway in A53T PD model mice, providing a fresh perspective on understanding the pathology of PD.