Function and Regulation of ALDH1A1-positive Nigrostriatal Dopaminergic Neurons in Motor Control and Parkinson's disease

National Institute On Aging

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Abstract

Parkinsons disease (PD), the most common degenerative movement disorder, particularly affects basal ganglia dopamine transmission. One of the most prominent pathological hallmarks of the disease is a preferential degeneration of dopaminergic neurons (DANs) located in the ventrolateral tier of substantia nigra pars compacta (SNc). While a member of aldehyde dehydrogenase family genes termed murine class 1 (cytosolic) aldehyde dehydrogenase (AHD2) or aldehyde dehydrogenase 1A1 (ALDH1A1) was reported some time ago to be selectively expressed by a subpopulation of DANs in the rodent ventral SNc, it is until 20 years later that research in postmortem human brains demonstrates a conserved topological distribution of ALDH1A1-positive DANs in the human SNc as well as a more severe loss of ALDH1A1-positive nigrostriatal DANs (ALDH1A1+ nDANs) in PD patients compared to the ALDH1A1-negative ones. ALDH1A1 is a key enzyme to mediate the biosynthesis of retinoic acids 5 and catabolism of reactive dopamine metabolites in DANs. The reduction of ALDH1A1 expression may contribute to the etiopathogenesis of PD, whereas an increase of ALDH1A1 levels protects against dopaminergic neurodegeneration. Although the expression and biochemical function of ALDH1A1 protein is extensively documented, less is known regarding the molecular, electrophysiological, anatomical, and physiological properties of ALDH1A1+ nDANs. We believe that a further in-depth study of ALDH1A1+ nDANs will bridge the gap toward a cell-type specific understanding of neural circuit mechanisms and treatment of PD.