**3. Parkinson's disease hallmarks**

PD is the most common movement neurodegenerative disorder characterized by numerous motor symptoms, including tremor, bradykinesia, rigidity and postural instability [138]. PD is twice as common in men than in women, and about 2% of the population above the age of 60 is affected by the disease [139]. PD is characterized by the severe loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and by the presence of intracytoplasmatic proteinaceous inclusions called Lewy bodies, which are primarily composed of fibrillary α-synuclein (SNCA), and ubiquitinated proteins within some remaining nigral neurons [140, 141].

Several evidences from autopsy studies showed that multiple processes are involved in cell death, including oxidative stress, mitochondrial dysfunction, neuroinflammation, excitotoxicity and accumulation of misfolded proteins due to proteasomal and autophagic impairment [142].

Data show that mitochondrial deficits occur in PD patient's brain neurons, platelets and lymphocytes [139],which play a critical role in the loss of dopaminergic neurons [143]. Furthermore, data suggest that mitochondrial dysfunction can be potentiated by defects in mitochondrial biogenesis caused by the deregulation of transcription factors, such as peroxisome proliferatoractivated receptor gamma coactivator1-alpha (PGC-1α) [144], which levels are decreased in postmortem brains of PD and in white blood cells [139]. Recent studies in post-mortem PD brain tissue showed that nigrostriatal axon terminals are dysfunctional, which can alter normal axonal transport. Also, the generation of ROS induces the damage of complexes I and III and protein oxidation in mitochondria and in cytoplasmic proteins, leading to mitochondrial dysfunction [145].

Several studies obtained in post-mortem PD brain tissue, human clinical imaging and fluid biomarker have demonstrated that neuroinflammation is a salient feature and probably an essential contributor to PD pathogenesis [145]. Inflammation associated with oxidative stress and cytokine-dependent toxicity has been described and can lead to both innate and adaptive immune responses. Immune responses can act a secondary response to cellular damage and/ or neuronal loss in the affected regions of the nervous system. These mechanisms imply not only a complex crosstalk between the CNS and the peripheral immune system but also interactions between the brain resident immune cells (microglial cells) and other brain cells (neurons, astrocytes, endothelial cells) [146]. Indeed, it has been described that PD brains show microglial activation and lymphocyte infiltration in the areas of degeneration and an increased expression of inflammatory cytokines with alterations in the composition of peripheral immune cells, suggesting the key role of neuroinflammation in PD.
