nonubiquitinated form only in the brains of oligomeric state)and in protection from patients with AR-JP, this accumulation oxidative damage (DJ-1 protein), with may be toxic. This along with the lack of mutations associated to PD LBs in this kind of pd has led to the hypothesis that ubiquitination of proteins Summarizing, in cases with non-apparent may play a role in their aggregation and familial genetic defects associated, along with precipitation into inclusion bodies an age-related tendency to accumulate oxidized damaged proteins, failure of the protective role to momentarily get ou UPS remove the way protein aggregates of insoluble, misfolded/abnormal proteins may une potentially toxic effect, if for any reason the degeneration of nigral cells in sporadic the proteasome is overwhelmed"and disease. Proteolytic stress with an cannot immediately act on their removal accompanying defect in protein handling is and at this regard it is noteworthy that crucial and the substantia nigra neurons are both monomeric and aggregated asyN ca particularly vulnerable due to their high bind to the proteasome and inhibit its content of dopamine. And this vulnerability is function if in excess-). In AR-JP, parkin is very likely due to the high basal rate of biquitination of all its substrates enzymatic and autooxidative machineries Therefore the cells cannot accumulate involved in dopamine oxidation them in LBs Cyclin E, p38 aminoacyl-tRNA complex, are yet recently- found substrates for parkin hose accumulation leads neuro Besides parkin and its substrates, there are yet other recently-di ed proteins playing roles in both protein degradation by the UPS (the Ub C-terminal hydrolase UCH-L1, which displays both polyubiquitinating activities depending on its Alzheimers disease (AD) The plaques in Ad are rich in amyloid B peptides (aB) that produced by In AD, the dominant sympt dementia lytic initially characterized by a loss of short-term precursor peptide(APP), a glycolipid located memory which gradually develops into a loss in the outer cell membrane. Three different of most higher faculties. Patients with A proteases, called a, B, and Y secretases, can display two types of protein deposits cleave APP at specific sites. Concomitant extracellular amyloi plaques and cleavage of APP by B and y secretase at intracellular neurofibrillary tangles. The specific sites can result in fragments that can atter neuropathological change is also misfold and form extracellular fibrils. These observed in a series of other neurological fibrils consist of B sheets. It is debated conditions that have been collectively named whether the fibrils are toxic through tauopathies and include some forms of formation of pores or whether th Parkinsonism, Picks disease, and boxing- extracellular amyloid deposits are the main induced dementia( Dementia pugilistica) culprits. The AB in plaques arises from specificnonubiquitinated form only in the brains of patients with AR-JP, this accumulation may be toxic. This along with the lack of LBs in this kind of PD has led to the hypothesis that ubiquitination of proteins may play a role in their aggregation and precipitation into inclusion bodies (the inclusions may even have a primary protective role to momentarily ‘get out of the way’ protein aggregates of insoluble, potentially toxic effect, if for any reason the proteasome is “overwhelmed” and cannot immediately act on their removal – and at this regard it is noteworthy that both monomeric and aggregated αSYN can bind to the proteasome and inhibit its function if in excess-). In AR-JP, parkin is usually inactivated and cannot act in the ubiquitination of all its substrates. Therefore the cells cannot accumulate them in LBs. • Cyclin E, p38 subunit of the aminoacyl-tRNA complex, are yet recently- found substrates for parkin whose accumulation leads also to neuronal apoptosis. Besides parkin and its substrates, there are yet other recently-discovered proteins playing roles in both protein degradation by the UPS (the Ub C-terminal hydrolase UCH-L1, which displays both deubiquitinating and polyubiquitinating activities depending on its Alzheimer’s disease (AD) In AD, the dominant symptom is dementia, initially characterized by a loss of short-term memory which gradually develops into a loss of most higher faculties. Patients with AD display two types of protein deposits: extracellular amyloid plaques and intracellular neurofibrillary tangles. The latter neuropathological change is also observed in a series of other neurological conditions that have been collectively named tauopathies and include some forms of Parkinsonism, Pick’s disease, and boxing￾induced dementia (Dementia pugilistica). oligomeric state) and in protection from oxidative damage (DJ-1 protein), with mutations associated to PD. Summarizing, in cases with non-apparent familial genetic defects associated, along with an age-related tendency to accumulate oxidized damaged proteins, failure of the UPS to adequately remove misfolded/abnormal proteins may underlie the degeneration of nigral cells in sporadic disease. Proteolytic stress with an accompanying defect in protein handling is crucial and the substantia nigra neurons are particularly vulnerable due to their high content of dopamine. And this vulnerability is very likely due to the high basal rate of protein oxidation which is due to the enzymatic and autooxidative machineries involved in dopamine oxidation. The plaques in AD are rich in amyloid β peptides (Aβ) that are produced by proteolytic cleavage of the amyloid precursor peptide (APP), a glycolipid located in the outer cell membrane. Three different proteases, called α, β, and γ secretases, can cleave APP at specific sites. Concomitant cleavage of APP by β and γ secretase at specific sites can result in fragments that can misfold and form extracellular fibrils. These fibrils consist of β sheets. It is debated whether the fibrils are toxic through formation of pores or whether the extracellular amyloid deposits are the main culprits. The Aβ in plaques arises from specific