Determinants of selective neuronal vulnerability in Parkinson's disease

Parkinson´s disease (PD) is the second most frequent neurodegenerative disease affecting the population older than 65 years old. This incidence will greatly increase due to the progressive aging of the population in the coming years. PD diagnosis is made when there is a 50-60% dopaminergic cell loss in the substantia nigra pars compacta (SNc) and the striatal dopamine loss reaches around 70-80%, coinciding with the onset of classical parkinsonian motor signs: tremor, rigidity and slowness of movement. A significant proportion of patients present non-motor symptoms, generally associated to disfunction of non-dopaminergic regions, which can appear before, around or after diagnosis (10-15 years). Therefore, in PD both dopaminergic and non-dopaminergic groups are affected, but the motor manifestations are the main reason for consultation and causes the greatest disability for many years. There is a large heterogeneity within dopaminergic neural groups in terms of morphology, metabolism, molecular pattern, protein accumulation, inflammation levels, protein expression, etc. In this review we discuss different factors that could explain the special vulnerability of certain dopaminergic neurons in the SNc. Knowledge on the mechanisms and underlying factors of this selective vulnerability of the ventrolateral dopaminergic neuros of the SNc is essential for developing neuromodulatory and/or neuroprotective therapies, leading in turn to halt or modify the neurodegenerative process in PD.