Parkinson's disease (PD) is characterised by selective and severe degeneration of the substantia nigra pars compacta and the locus coeruleus (LC), which underlies the most prominent symptoms. Although α-synuclein accumulation has long been established to play a causal role in the disease, it alone cannot explain the selective degenerative pattern. Recent evidence shows that the selective vulnerability could arise due to the large presence of cytosolic catecholamines and Ca2+ ions in the substantia nigra pars compacta and LC specifically that can be aberrantly affected by α-synuclein accumulation. Moreover, each has its own toxic potential, and disturbance of one can exacerbate the toxic effects of the others. This presents a mechanism unique to these areas that can lead to a vicious degenerative cycle. Interestingly, in familial variants of PD, the exact same brain areas are affected, implying the underlying process is likely the same. However, the exact disease mechanisms of many of these genetic variants remain unclear. Here, we review the effects of the PD-related genes Parkin, PINK1 and DJ-1. We establish that these mutant varieties can set in motion the same degenerative process involving α-synuclein, cytosolic catecholamines and Ca2+ . Additionally, we show indications that model organisms might not accurately represent all components of this central mechanism, explaining why Parkin, PINK1 and DJ-1 model organisms often lack a convincing PD-like phenotype.