In PD, some surviving nigral dopaminergic neurons contain cytosolic filamentous inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs). These hereditary forms account for ~4% of PD patients, who develop early-onset disease before the age of 50. In addition to the sporadic form, there are multiple familial forms of the disease linked to mutations in a number of genes. Sporadic (or idiopathic) forms of this disease account for about 95% of PD patients. However, this acceleration seems to be determined by a combination of genetic susceptibility and environmental factors. It is also unknown why the loss of the nerve cells is accelerated in PD. The detailed mechanism of the neuronal death is unknown. Epidemiological studies and pathological analyses revealed a mean age of onset of 70 years in sporadic PD. In clinical PD, the neuron loss is accelerated. Thus, if an unaffected person lives to be ~120 years old he (she) will probably develop PD. The “normal” rate of nigral cell loss is ~2,400 per a year. The symptoms of PD become apparent after more than ~70% of the dopaminergic neurons die. The substantia nigra consists of ~400,000 nerve cells, which begin to pigment after birth and are fully pigmented at age 18. This, in turn, can produce one or more of the classic signs of PD: resting tremor on one (or both) side(s) of the body generalized slowness of movement or difficulty initiating movement (bradykinesia/akinesia) stiffness of limbs (rigidity) and gait or balance problems (postural instability). Gradual degeneration of these cells causes a reduction in the dopamine content. PD is a slowly progressive malady that affects the neurons in the substantia nigra, a small area of cells in the midbrain. Based on these facts, PD is now considered an aging-related disease. Approximately 1% of the population at 65–70 years of age is affected by PD, whereas the number of PD patients increases to 4–5% in 85-year-olds. The prevalence of PD is much greater among those who are at least 65 years old. The probability of sporadic PD development increases with age, with only a small percentage of patients diagnosed before the age of 50. It is estimated that ~1.5 million Americans are affected by PD. Parkinson’s disease, PD, is the most common aging-related movement disorder and the second most common neurodegenerative disorder after Alzheimer’s disease (AD). PARKINSON’S DISEASE AS A TYPICAL SYNUC-LEINOPATHY Fink to the field and presents some recent developments in this exciting area.ġ. This review focuses on the contributions of Prof. The molecular basis of Parkinson’s disease appears to be tightly coupled to the aggregation of α-synuclein and the factors that affect its conformation. The aggregation process appears to be branched, with one pathway leading to fibrils and another to oligomeric intermediates that may ultimately form amorphous deposits. There is a strong correlation between the conformation of α-synuclein (induced by various factors) and its rate of fibrillation. A number of intrinsic and extrinsic factors that either accelerate or inhibit the rate of α-synuclein aggregation and fibrillation in vitro are known. Besides the membrane-bound form, other critical conformations include a partially-folded state that is a key intermediate in aggregation and fibrillation, various oligomeric species, and fibrillar and amorphous aggregates. A number of different conformational states of α-synuclein have been observed. When isolated in solution, the protein is intrinsically disordered, but in the presence of lipid surfaces α-synuclein adopts a highly helical structure that is believed to mediate its normal function(s). α-Synuclein is abundant in various regions of the brain and has two closely related homologs, β-synuclein and γ-synuclein. Furthermore, α-synuclein was identified as the major component of amyloid fibrils found in Lewy body and Lewy neurites, the characteristic proteinaceous deposits that are the diagnostic hallmarks of PD. Rare familial cases of PD are associated with missense point mutations in α-synuclein, or with the hyper-expression of the wild type protein due to its gene duplication/triplication. Substantial evidence links α-synuclein, a small highly conserved presynaptic protein with unknown function, to both familial and sporadic PD. PD is a multifactorial disorder with unknown etiology, in which both genetic and environmental factors play important roles. Parkinson’s disease (PD) is a slowly progressive movement disorder that results from the loss of dopaminergic neurons in the substantia nigra, a small area of cells in the mid-brain.
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