Classically, Parkinson’s disease (PD) is considered to be a motor system affliction and its diagnosis is based on
the presence of a set of cardinal motor signs (e.g. rigidity, bradykinesia, rest tremor and postural reflex disturbance).
However, there is considerable evidence showing that non-motor alterations (e.g. anxiety, depression, sleep,
gastrointestinal and cognitive functions) precede the classical motor symptoms seen in PD. The management of these nonmotor
symptoms remains a challenge. A pattern of regional neurodegeneration that varies considerably depending upon
the neuronal population affected may explain the different symptoms. In fact, differential mechanisms of neuronal
vulnerability within the substantia nigra pars compacta (SNpc) suggests that factors other than location contribute to the
susceptibility of these neurons. In this review we discuss how these factors interact to ultimately target the SNpc.
Remarkably, this region consists of approximately 95% of the tyrosine hydroxylase (TH)-immunoreactive neurons in both
human and rat brains, and consequently this implicates elevated levels of dopamine metabolites, free radicals and other
hazard species in these neurons. An understanding of how these factors promote neuronal death may be useful for the
development of novel neuroprotective and/or neurorestorative strategies for PD.