IntroductionParkinson’s disease (PD) is the second most common neurodegenerative age-related disease, worldwide. Approximately 90% of cases are sporadic, thus less than 10% of PD cases follow inheritance pattern. Clinical diagnosis of PD is based on the presence of particular motor symptoms including bradykinesia, rigidity, abnormal posture, and resting tremor. Although pathological structures are recognizable in many domains of the cerebrum, like subthalamic nucleus and hippocampus, motor symptoms principally derive from the death of substantia nigra (SN) dopamine (DA) neurons. The proportion of DA neurons degeneration in the substantia nigra pars compacta has been related to the duration of the disease (what do you mean duration?), and the cell apoptosis followed a precise order (need to rephrase). It has been shown that the progressive deterioration of susceptible SN DA neurons may arise from cellular abnormalities as a result of misfolding and aggregation of the synaptic protein alpha synuclein (?-syn) (A), disruption of the ubiquitin and chaperone mediated autophagy system (B), mitochondrial (C) and ER (D) homeostasis, fragmentation of the Golgi apparatus (E) and  excessive permeability of cell membrane (F). (P. Damier, 1999).Why is DA so important for the initiating movements?Firstly the primary structure which interfaces the DA neurons with the motor control system, is basal ganglia (BG). The term basal ganglia refers to a vast and functionally diverse set of nuclei that lie deep within the cerebral hemispheres and includes caudate, putamen and the globus pallidus, substantia nigra and the subthalamic nucleus. Those make a subcortical circle which connects most of the cortical territories with the upper motor neurons in the primary motor and premotor cortex and in the brain stem. The neurons in this circle respond in prevision of and during movements, thus they have direct consequences on upper motor neurons which are essential for regular voluntary movements (Dale Purves, 2011). Under normal conditions, dopamine appears to initiate an excitatory effect upon striatal neurons of the ‘direct’ pathway to the internal globus pallidus, and an inhibitory effect upon neurons of the ‘indirect’ pathway to the external globus pallidus. As a result, the indirect pathway modulates the effects of the direct (Fig. 1). Loss of striatal domapine then causes abnormalities both in the direct and indirect pathways, causing the patients’   inability to control their movements.Figure 1:  Basal ganglia-thalamo-cortical circuit schematic in the normal and parkinsonian states. Thickness of the arrows represents the strength of connections. Loss of substantia nigra neurons promote increased thalamic inhibition.https://jamanetwork.com/journals/jamaneurology/fullarticle/1569975Factors which facilitate DA neurons degeneration in PD Alpha synuclein (?-syn) aggregation (A)From the neuropathological point of view, PD is defined by DA cell loss in the substantia nigra and the presence of Lewy bodies and Lewy neurites. An important discovery in 1997 was that a mutation in the ?-syn gene was responsible for some inherited forms of PD, together with the finding that Lewy bodies (LBs), appeared to be the key neuropathological features of sporadic PD (Polymeropoulos M, 1997). This was a major breakthrough that dramatically changed our view of PD pathogenesis, which has become in many respects “synuclein-centric”. ?-syn is a small 140 aa protein normally enriched in the presynaptic compartment (Iwai A, 1995 ) where it is thought to promote the formation of the SNARE complex, thereby regulating vesicle dynamics and trafficking and, hence, neurotransmitter release. (Burré J, 2010)The term “Lewy bodies” is used to describe those eosinophilic, cyto-plasmic inclusions of fibrillar, misfolded proteins, which are primarily composed of misfolded/aggregated ?-syn and appeared in affected brain areas such as SN (Fig. 2). Lewy bodies and Lewy neurites are also found in other brain regions, such as the dorsal motor nucleus of the vagus, the nucleus basalis of Meynert, and the locus coeruleus. (Maria Grazia Spillantini, May 1998) Figure 2: Immunoreactivity in the substantia nigra of patients with Parkinson disease (A,B,D,E,F,G) and Lewy body disease (C). Classical Lewy bodies (A–E) and swollen neurites (F) were heavily immunostained.https://academic.oup.com/jnen/article/61/3/245/2609962Abnormalities in ?-syn regulation in sporadic PD are probably linked with pathological gain of function in DA neurons rather than a loss of their function. In model systems with ?-syn overexpression, aggregation and deposition preceded DA neurons death. Therefore strategies which reduced the aggregative process repressed neurodegeneration and improved motor deficits in many species, including invertebrates (nematodes and flies), rodents, and non-human primates (Lashuel H, 2013). More scientific reports indicate that soluble oligomers and protofibrils, which are formed relatively early during the fibrillation process of ?-syn, seem to be particularly toxic to DA neurons because they can alter key cellular functions, including mitochondrial and ER dysfunction, as well as promote fragmentation of the Golgi apparatus and imbalance in membrane permeability (Fig. 3). (Winner B, 2011)Figure 3: Possible Causes and Consequences of a- syn aggregation in PD. The fibrillation process involves the aggregation of misfolded monomers into dimers and together with overexpression of the protein lead to small oligomeric species that can be stabilized by ? sheet-like interactions. At this stage, synuclein aggregation together with ubiquitin and other cytoskeletal proteins, evolve to higher molecular weight insoluble protofibrils and culminates in the formation of amyloid-like fibrils which facilitate pathological formations such as Lewy Bodies.https://www.sciencedirect.com/science/article/pii/S0896627316300587#bib32Disruption of the UPS – CMA and autophagy system (B)Among the factors initiating and/or favoring fibrillation, and therefore, DA cell degeneration, is the imbalance between the expression and degradation levels of ?-synuclein. In particular, dysfunction of the ubiquitin proteasome system (UPS), chaperone-mediated autophagy (CMA) and macro-autophagy pathways may be involved in inefficient elimination of higher molecular weight of ?-synuclein (such as oligomers and fibrils) (Fig. 4). In addition, biopsies in post mortem PD brains indicate approximately 40% reduction in UPS activity, specifically in the DA substantia nigra neurons. (McNaught KS, 2001). Consequently, any abnormalities in those systems enhance the a-synuclein aggregation and neurotoxicity of PD. (Nixon, 2013)  Figure 4:  Those three systems regulate co-ordinately to maintain intracellular protein homeostasis. The chaperones are composed of heat-shock proteins, represent the first line of defense in providing the adequate folding of proteins. When a native folding state cannot be accomplished, the chaperones will direct the misfolded protein for degradation by the proteasome. The autophagy process involves a phagophore which matures into a double-membrane structure called autophagosome that engulfs the misfolded protein substrate. The autophagosome then fuses with a lysosome to form autolysosomes, and the misfolded protein is hydrolysed by acidic lysosomal hydrolases.https://www.researchgate.net/figure/Protein-QC-systems-The-chaperone-ubiquitin-proteasome-and-autophagy-systems-function_fig1_236196744Mitochondrial homeostasis (C)Enlarged mitochondria with disrupted cristae have been observed in nigral neurons from PD patients, which confirms the view that mitochondrial quality control is defective in sporadic PD (Greene JC, 2003 April). Mitochondrial quality control refers to cellular mechanisms that ensure proper functioning of the mitochondrial network, which is essential for DA neurons (and generally cellular) physiology and survival. It involves several functional aspects, including damage prevention and repair mechanisms, autophagic elimination of dysfunctional/damaged organelles (known as mitophagy), and neosynthesis of mitochondrial DNA- and nuclear DNA-encoded mitochondrial proteins for mitochondria biogenesis. In addition, mitochondrial dysfunction can cause ATP depletion and necrosis, and these organelles are also involved in the regulation of apoptotic cell death. Moreover, mitochondria are the primary source of reactive oxygen species (ROS) production in cells. Under normal conditions, up to 2% of the total cellular mitochondrial O2 consumption may be related to the generation of ROS, which is known that in high rates lead to loss of cellular function, and eventually apoptosis. The brain is particularly vulnerable to ROS effects, due to its high oxygen demand. Biological macromolecules such as lipids, proteins and nucleic acids isolated from substantia nigra tissue of patients with PD show increased oxidative damage to DA neurons (reference?). Taken together, these findings have placed the abnormal mitochondrial homeostasis to the focus of current neuronal cell death research. (C. Henchcliffe, 2008) (G.H. Kim, 2015).Endoplasmic Reticulum homeostasis (ER) (D)Evidence of ER stress is found in post-mortem substantia nigra tissue from sporadic human PD cases and in most animal models of the disease, implicating its significance in DA neurons survival. ER is crucial to protein folding in eukaryote cells, and any perturbations altering ER homeostasis can result in the disruption of the folding process and accumulation of misfolded or unfolded proteins. Accumulation of unfolded and/or misfolded proteins in the ER lumen induces ER stress. To withstand such possible lethal conditions, intracellular signaling pathways together termed as the unfolded protein responses (UPR) are activated. The UPR include translational attenuation, induction of ER resident chaperones, and degradation of misfolded proteins through the ER-associated degradation. In case of severe and/or extended ER stress, cellular signals proceed to cell death are activated. Taking these into account, strong evidence suggests that ER stress induced by protein aggregation is implicated in PD and enhances DA neurons depletion. (Wang HQ, 2007) (Chee Yeun Chung, 06 Nov 2013).Fragmentation of the Golgi apparatus (E)In Parkinson’s disease, fragmentation is believed to be the consequence of an ER–Golgi transport imbalance and/or of cytoskeleton modifications. Aggregates of ?-syn may inhibit ER-to-Golgi transport, thus reducing the levels of vesicular monoamine transporter to synapse. This results in the accumulation of toxic dopamine in the cytosol, causing oxidative stress and, finally, neuronal cell death (Emma Martínez-Alonso, 2013). Moreover, data indicate that neuronal Golgi fragmentation is an early and probably irreversible sign of neurodegeneration, caused by apoptosis induction. The Golgi apparatus undergoes irreversible fragmentation during apoptosis, partially as a result of caspase-mediated pathway. At the same time, Golgi structure and orientation also regulates cytoskeletal changes which further promote apoptosis. Consequently, damage to neuronal Golgi structure plays an important role in degeneration of DA neurons. (Shields, April 2007) (Yukio Fujita, September 2006, Volume 112, Issue 3).Excessive permeability of cell membrane (F)A-syn and lipids interaction in the neuronal cell membrane has been proposed to be an important step in the process of oligomerization and neurotoxicity (JD Perlmutter, October 2009). The oligomers might interfere with the normal function of cellular membranes and result in the formation of pore-like structures. Those abnormal membrane formations facilitate channel-like activity and lead to excessive calcium influx that is neurotoxic. (Masliah, March 2012).  Increased calcium activates a number of enzymes, e.g. – ATPases (thereby hastening ATP depletion), phospholipases (which cause membrane damage), proteases (which break down both membrane and cytoskeletal proteins), and endonucleases (which are responsible for DNA and chromatin fragmentation). This suggests that Ca2+ could be a key player in coordinating complex organelle networks to ultimately achieve metabolic interactions, intracellular signalling, cellular maintenance and regulation of cell survival in PD. (Sofia V. Zaichick, 2017 ).ConclusionThe pathological signs of Parkinson’s disease (PD) include the loss of dopaminergic (DA) neurons in the mesencephalon and the presence of Lewy bodies in affected neurons. The exact cause of this neuronal loss is partially unknown, but recent human post-mortem studies have suggested that, in PD, nigral DA neurons die by apoptosis. Therefore, a DA neuron- rescue mechanism could be another promising pharmacological target for PD in the near future.ReferencesAbeliovich A, S. Y.-L. (2000). Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000 Jan;25(1):239-52., 239-252.Anglade P, V. S.-A. (1997). Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histology Histopathology, 25-31.Anglade P, V. S.-A.-P. (1997). Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol. 1997 Jan;12(1):25-31, 25-31.Burré J, S. M. (2010). 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