found in around 50% of the patients with AR JP ( Juvenile or early-onset Parkinsonism) Parkin-associated endothelial-like also known as Autosomal Recessive Parkinsons receptor(PaeI) receptor, putative G Disease [ARPD], one of the most common familial forms of PD. Interestingly, with a few polypeptide. When overexpressed exceptions, AR-JP is characterized by a lack aggregates and parkin can ubiquitinate of lBs and target it for its degradation. Its accumulation elicits cell-death The RING finger domain is involved, most promoted by the activation of the probably, in recruitment of the E2 component Unfolded Protein Response (UPR)in of the ubiquitination machinery, while the UBL the ER (a stress-responsive pathway that increases biosynthesis of facilitating transfer of the polyubiquitinated in response to substrate(s) to the degrading machinery. It accumulation misfolded/ appears that Parkin serves as a common, RING denatured/mutated proteins in this finger-containing component shared by organelle). group of putative, yet to be discovered, SCl (overexpression of Parkin can like complexes. Most of the point mutations rescue cells from the UPR elicited described in Parkin reside in its RING-IBR by a variety of stresses(H202 (In Between-RINGS)-RING domain and UV, osmolarity, heat shock, etc) result in its inactivation. Some mutations may fact that also suggests its role in reduce the activity of the enzyme (the clearing up cells from certain autocatalytic one and/or the one displayed toward the exogenous substrates)whereas others may affect other mechanisms, such as interaction of the E3 with essential partners a-synuclein (asyN) and its associated protein Synphilin-1 A crucially important development in our proteins of yet unclear role but found nderstanding of parkin function is the n protein inclusions(LBs)in patients identification of its native cellular with sporadic, late-onset PD. substrates. The overriding hypothesis is that a defect in parkin will result in accumulation of this protein(s), which is toxic to the dopamine dopaminergic neurons. Several substrates have neurotransmission/release via been identified that are ubiquitinated by effects on vesicular storage Parkin, yet it is not clear whether is the Wild-typ aSyN accumulation of one or several of these monomeric but at high proteins that underlies the pathogenesis of concentrations this familial form of PD oligomerizes to B-pleated sheets known as protofibrils Identified substrates for Parkin: These can further aggregate precipitate myloid Cell Division Control related protein fibrils that are present in (CDCrel-1), very likely involved in the the Lewy Bodies(hallmark of regulation of transmitter release via its role in regular Mutations in the nonglycosilated 14 dynamics. Parkin also has other aSyN are related to the pathogenesis of potential substrates related to PD but, in particular, a novel 22 kDa form such as synaptotagmin D been found to be a direct substrate for filaments parkin. Since aSp22 accumulates in afound in around 50% of the patients with AR￾JP (Juvenile or early-onset Parkinsonism), also known as Autosomal Recessive Parkinson’s Disease [ARPD]), one of the most common familial forms of PD. Interestingly, with a few exceptions, AR-JP is characterized by a lack of LBs. The RING finger domain is involved, most probably, in recruitment of the E2 component of the ubiquitination machinery, while the UBL serves as a proteasome binding thus facilitating transfer of the polyubiquitinated substrate(s) to the degrading machinery. It appears that Parkin serves as a common, RING finger-containing component shared by a group of putative, yet to be discovered, SCF￾like complexes. Most of the point mutations described in Parkin reside in its RING-IBR- (In Between-RINGS)-RING domain and result in its inactivation. Some mutations may reduce the activity of the enzyme (the autocatalytic one and/or the one displayed toward the exogenous substrates) whereas others may affect other mechanisms, such as interaction of the E3 with essential partners. A crucially important development in our understanding of Parkin function is the identification of its native cellular substrates. The overriding hypothesis is that a defect in Parkin will result in accumulation of this protein(s), which is toxic to the dopaminergic neurons. Several substrates have been identified that are ubiquitinated by Parkin, yet it is not clear whether is the accumulation of one or several of these proteins that underlies the pathogenesis of this familial form of PD. Identified substrates for Parkin: • Cell Division Control related protein (CDCrel-1), very likely involved in the regulation of transmitter release via its role in regulating synaptic vesicle dynamics. Parkin also has other potential substrates related to synaptic transmission, such as synaptotagmin IX and actin filaments. • Parkin-associated endothelial-like receptor (PaeI) receptor, putative G protein-coupled transmembrane polypeptide. When overexpressed, aggregates and parkin can ubiquitinate and target it for its degradation. Its accumulation elicits cell-death promoted by the activation of the Unfolded Protein Response (UPR) in the ER (a stress-responsive pathway that increases biosynthesis of chaperones in response to accumulation of misfolded/ denatured/mutated proteins in this organelle). **(overexpression of Parkin can rescue cells from the UPR elicited by a variety of stresses (H2O2, UV, osmolarity, heat shock, etc), fact that also suggests its role in clearing up cells from certain proteins that are toxic when accumulate). • α-synuclein (αSYN) and its associated protein Synphilin-1, proteins of yet unclear role but found in protein inclusions (LBs) in patients with sporadic, late-onset PD. o αSYN is thought to regulate/participate in dopamine neurotransmission/release via effects on vesicular storage. Wild-type αSYN is monomeric but at high concentrations, it oligomerizes to β-pleated sheets known as protofibrils. These can further aggregate and precipitate as amyloid fibrils that are present in the Lewy Bodies (hallmark of sporadic, late-onset PD). Mutations in the nonglycosilated 14 kDa αSYN are related to the pathogenesis of PD but, in particular, a novel 22 kDa form of O-glycosilated αSYN (αSp22) has been found to be a direct substrate for parkin. Since αSp22 accumulates in a