Anxa1+ dopamine neuron vulnerability defines prodromal Parkinson's disease bradykinesia and procedural motor learning impairment

Abstract

Progressive degeneration of dopamine neurons (DANs) defines Parkinsons disease (PD). However, the identity and function of the most vulnerable DAN populations in prodromal PD remain undefined. Here, we identify substantia nigra DANs with Annexin A1 (Anxa1) expression as selectively vulnerable across multiple prodromal PD models and significantly reduced in patient-derived DANs. We found that Anxa1+ DANs have a unique functional profile, as they do not signal reward or reinforce actions, and they are not necessary for motivated behavior. Instead, activity of Anxa1+ DAN axons correlates with vigorous movements during self-paced exploration, yet their silencing only disrupts a subset of action sequences that mirror a PD bradykinesia profile. Importantly, Anxa1+ DANs are essential for procedural learning in a maze task and for motor learning of dexterous actions. These findings establish the early vulnerability of Anxa1+ DANs in PD, whose function can explain prodromal bradykinesia and impairments in procedural motor learning.