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In support of this hypothesis, it has been Quinapyramine found that mice deficient in the PD-associated gene Parkin show neuronal as well as astrocytic mitochondrial alterations [24, 25]. Of note, respiratory dysfunction in astrocytes may lead to a reduction of the neurotrophic support during neuronal development, a phenomenon that could contribute to the induction of neuronal deficits [26]. Another protein whose mutations have been found to induce rare forms of autosomal recessive parkinsonism is DJ-1. This latter seems to function as a redox-sensitive molecular chaperone, whose loss of function may induce oxidative stress and consequently mitochondrial damage [27] that are associated with deficits in mechanisms to counteract reactive oxygen species (ROS) formation [28]. DJ-1 knockout animals show an enhanced Selleckchem GDC-0449 sensitivity to the exposure of mitochondrial toxins; however, they do not develop PD-like pathological alterations per se. Instead, expression of mutant forms of leucine-rich kinase 2 (LRRK2), that are the most common cause for the onset of familial PD, only produces subtle alterations in mitochondria morphology and integrity in vivo, although it has been hypothesized that the protein may also regulate mitochondrial dynamics [27]. All these studies point toward mitochondrial dysfunction as a relevant pathological mechanism in the induction of neuronal dysfunction and degeneration in the PD brain. Normal mitochondrial activity is fundamental to maintain neuronal homeostasis and organelle turnover and defects in these processes can induce neurotoxicity through oxidative mechanisms or by promoting ��-synuclein misfolding and oligomerization [29]. Therefore, www.selleckchem.com/products/MS-275.html whether ��-synuclein synaptic deposition is the priming event for the onset of PD or vice versa mitochondrial deficits anticipate and trigger ��-synuclein pathology and dopamine neuron degeneration is still an open question. In this review we will describe the critical interplay between ��-synuclein synaptic accumulation and mitochondrial dysfunction in PD and try to unfold which comes first in the pathogenesis of PD. 2. The Synaptic Pathology of ��-Synuclein in PD In the PD brain, LBs are mainly found in sites of neuronal loss, that is, the substantia nigra and locus coeruleus, so they were hypothesized to play a pathogenic role in neuronal degeneration. However, despite the negative correlation occurring between nigral neuronal density and ��-synuclein burden in the PD brain, this was found to be unrelated to no relationship with Hoehn and Yahr stage or disease duration [30]. These findings, although supporting that the severity of neuron degeneration in the substantia nigra is closely coupled to ��-synuclein burden, have undermined the above presented hypothesis. Moreover, it has to be emphasized that the majority of degenerating neurons do not contain LBs. Neurons may show morphological, dendritic, and synaptic alterations or biochemical changes in the absence or presence of LBs.