Selective neuronal vulnerability in Parkinson disease

Clinical Parkinson disease (cPD) is associated with both distributed Lewy pathology (LP) and neuronal death. There are no proven strategies of modifying either feature of the disease.Although there is consistency in the brain regions manifesting LP, there is considerable variability in its sequencing and severity. Moreover, the relationship between LP and the pathophysiology underlying symptoms is uncertain.The distribution of LP in cPD is not consistent with a simple prion model in which the spread of LP is retrograde and determined solely by the brain connectome.Neuronal death in cPD is less well characterized, but it is seen first in the substantia nigra, appearing later in a subset of neurons in the diencephalon, telencephalon and brainstem. Importantly, the pattern of neuronal death differs considerably in staging and to a lesser extent in distribution from that of LP.Many of the neurons that die in cPD exhibit a common set of traits, which include a long, highly branched axon, autonomous spiking, elevated calcium entry and basal mitochondrial oxidant stress. This set of traits may make these neurons vulnerable to cell death in association with LP, ageing, genetic mutations associated with cPD and/or environmental toxins.Therapeutic strategies aimed at altering the features of neurons that make them vulnerable to death and LP have the potential to slow or stop the progression of cPD.