The assumption that the PD neurodegenerative process begins in the dopaminergic substantia nigra has been seriously challenged by recent publications. New different studies have provided evidence in support of a lower brainstem origin, predating involvement of the nigra. In addition to the prominent loss of nigro-striatal dopamine neurons, there is also degeneration of nor-epinephrine neurons in the locus coeruleus, cholinergic neurons in the nucleus basalis of Meynert, the dorsal motor nucleus of the vagus, and involvement of the spinal cord and peripheral autonomic system. There is dysfunction of multiple neurotransmitter systems and research is underway to determine if therapeutic restoration of these transmitters can provide benefit in PD. We discuss these biochemical and pathological aspects inside the most classic clinical assumption of PD as a dopaminergic depletion-induced disease
