ALDH1A1-Negative Nigrostriatal Dopaminergic Neuron Subtypes in Parkinsons Disease

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Parkinson’s disease (PD) is pathologically characterized by the progressive loss of midbrain dopaminergic neurons (DANs), particularly those in the substantia nigra pars compacta (SNc). We and others have shown that aldehyde dehydrogenase 1A1-positive (ALDH1A1+) DANs in the ventral tier of the SNc are especially vulnerable in individuals with PD, as well as in rodent and primate PD models. Recent single-cell and single-nucleus RNA sequencing studies have revealed multiple molecularly distinct midbrain DAN subtypes. Although DANs regulate a wide range of motor and non-motor behaviors, the specific contributions of individual DAN subtypes remain poorly understood. ALDH1A1+ DANs make up approximately two-thirds of the DANs in the human and rodent SNc, and about one-third of those in the rodent ventral tegmental area (VTA). In the SNc, ALDH1A1+ DANs are essential for locomotor control and motor skill learning in rodents. By contrast, ALDH1A1– DANs, located predominantly in the dorsal tier of the SNc, are also affected in PD but are less vulnerable than their ALDH1A1+ counterparts. However, the functional roles of ALDH1A1– SNc DANs in motor control and learning remain unclear. Because calbindin 1 (CALB1) is expressed mainly in ALDH1A1– DANs, we used an intersectional genetic strategy with ThFlp; Calb1IRESTCre double knock-in mice, together with a Cre- and Flp-dependent DREADD system, to selectively inhibit CALB1+ DAN subtypes during behavioral testing. In parallel, we generated ThFlp; Aldh1a1CreERT2 double knock-in mice to selectively manipulate ALDH1A1+ SNc DANs. Our findings demonstrate that both ALDH1A1+ and CALB1+ SNc DANs contribute significantly to motor control and motor skill learning. These results identify two molecularly distinct SNc DAN subtypes as important regulators of movement and highlight them as potential therapeutic targets for PD-related motor dysfunction.