A Vulnerable Subtype of Dopaminergic Neurons Drives Early Motor Deficits in Parkinson’s Disease

In Parkinson's disease, dopaminergic neurons (DANs) in the midbrain gradually degenerate, with ventral substantia nigra pars compacta (SNc) DANs exhibiting greater vulnerability. However, it remains unclear whether specific molecular subtypes of ventral SNc DANs are more susceptible to degeneration in PD, and if they contribute to the early motor symptoms associated with the disease. We identified a subtype of Sox6+ DANs, Anxa1+, which are selectively lost earlier than other DANs, and with a time course that aligns with the development of motor symptoms in MitoPark mice. We generated a knock-in Cre mouse line for Anxa1+ DANs and showed differential anatomical inputs and outputs of this population. Further, we found that the inhibition of transmitter release in Anxa1+ neurons led to bradykinesia and tremor. This study uncovers the existence of a selectively vulnerable subtype of DANs that is sufficient to drive early motor symptoms in Parkinson’s disease. Single-nucleus RNA profiling of the ventral midbrain of MitoPark mice, their littermate controls and C57BL/6 mice at 8, 16, and 24 weeks of age (8 mice in each group; 4 males and 4 females). Two animals were used for each sample. For instance, in RA004, two 8-week-old male MitoPark mice were combined.