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This stage is thought to coincide with the onset of motor signs. In advanced phases, ��-synuclein deposits can be found in basal mesencephalon, allocortex, neocortex, and the cortical transentorhinal region and premotor areas (Stage 5) and then proceed forward to first order as well as primary sensory association areas of the neocortex and premotor zone (stage 6). A link between the onset of clinical symptoms and ��-synuclein pathology is further supported by studies indicating that a plethora of typical PD premotor signs encompassing olfactory dysfunctions, sleep disorders, cardiovascular dysfunction, and gastrointestinal and urinary abnormalities may still be attributed to ��-synuclein accumulation affecting both central and peripheral neuronal cells [14]. It has been found that 90% or even more of ��-synuclein aggregates in the brain of PD patients GDC-0449 supplier are located at the presynapses in the form of very small deposits. In parallel, dendritic spines are retracted, whereas the presynapses are relatively preserved, suggesting that neurotransmitter deprivation is an early event in PD pathogenesis. Several lines of evidence from rodent models of PD have confirmed that ��-synuclein aggregation Quinapyramine may damage neurons starting from the synaptic compartment and this leads to a consequent retrograde axonal damage terminating in neuronal cell degeneration with a dying back fashion [15, 16]. Therefore, the synaptic damage related to ��-synuclein deposition could play a primary role in coaxing the onset of motor symptoms and neuronal loss in PD. In this scenario, it is though relevant to consider that the polarity and correct functionality of neurons depend on an efficient transport of mitochondria to areas of high energy consumption such as presynaptic sites [17]. Furthermore, the selective vulnerability of substantia nigra pars compacta neurons in PD has been postulated to depend on the peculiar ��energy-demanding�� physiology of these cells [18]. Dopaminergic nigrostriatal neurons display an extended axonal field and the number of synapses for each axon is orders of magnitude higher than that of other neurons [19]. They generate autonomous selleck kinase inhibitor action potentials by unusual engaging of L-type Ca2+ channels, thus requiring the activation of ATP-dependent Ca2+ pumps to maintain proper cytoplasmic Ca2+ homeostasis [20]. To afford this gargantuan energy demand, mitochondria and endoplasmic reticulum in substantia nigra pars compacta dopaminergic neurons generate reactive oxygen species (ROS) which are constantly neutralized by antioxidant systems [21]. However, nigral dopaminergic neurons, inter alia, are especially vulnerable to oxidative processes, as they present elevated amounts of iron but reduced antioxidative players [22, 23].