Despite this regulatory mechanism, the vulnerability of SN DA neurons may nevertheless increase due to an altered spontaneous firing activity of DA neurons, Ca<sup>2+</sup> dishomeostasis, mitochondrial stress, high dendritic arborization, aggregation of α-synuclein (α-syn), α-syn mutations, reduced levels of calbindin protein, etc. Although the intraneuronal accumulation and the spreading of misfolded α-syn is a hallmark of full-blown Parkinson's disease, the effects produced by α-syn aggregation on neuronal functionality at the early onset of neurodegeneration are still of debate. The gene discussed is CALB1; the disease is Parkinson disease.