Alpha-synuclein, LRRK2 and Parkinson's Disease
Alpha-synuclein, LRRK2 and Parkinson's Disease
The ubiquitin–proteasome system (UPS) is one of the main pathways in cells responsible for the removal and recycling of undesired proteins. While the stability of both α-syn and LRRK2 is regulated by the UPS pathway; α-syn aggregates may cause impairment of UPS activities, which may lead to the accumulation of ubiquitinated proteins in neurons. Interestingly, G2019S LRRK2 protein is also sequestered as ubiquitin-positive clusters in neurons of aging animals. The accumulation of G2019S LRRK2 and ubiquitin-positive protein aggregates in aged mice indicate that overexpression of LRRK2, especially the G2019S mutation, may impair UPS activity in neurons. More interestingly, coexpression of PD-related A53T α-syn and G2019S LRRK2 seem to further damage UPS activities and accelerate the deposition of both α-syn and LRRK2 protein aggregates.
Autophagy is the other essential machinery in cells that is responsible for the removal of damaged organelles and large protein aggregates. Various malfunctions of autophagy pathways have been reported in PD, in which both α-syn and LRRK2 are involved. The α-syn A53T mutation seems to interfere with the chaperone-mediated autophagy and macroautophagy pathways in cells, which impairs the clearance of α-syn aggregates. LRRK2 is also implicated in regulating autophagy induction and flux rates in cell cultures. In particular, loss of LRRK2 leads to excessive accumulation of marker proteins involved in the induction of autophagy in cells from the kidney and lung. However, no overt impairment of the autophagy pathway is observed in LRRK2-deficient neurons. Nonetheless, future studies may focus on identifying the molecular partners of LRRK2 in the autophagy pathway in order to fully understand the contribution of LRRK2 in this fundamental cellular process.
The Ubiquitin–proteasome System
The ubiquitin–proteasome system (UPS) is one of the main pathways in cells responsible for the removal and recycling of undesired proteins. While the stability of both α-syn and LRRK2 is regulated by the UPS pathway; α-syn aggregates may cause impairment of UPS activities, which may lead to the accumulation of ubiquitinated proteins in neurons. Interestingly, G2019S LRRK2 protein is also sequestered as ubiquitin-positive clusters in neurons of aging animals. The accumulation of G2019S LRRK2 and ubiquitin-positive protein aggregates in aged mice indicate that overexpression of LRRK2, especially the G2019S mutation, may impair UPS activity in neurons. More interestingly, coexpression of PD-related A53T α-syn and G2019S LRRK2 seem to further damage UPS activities and accelerate the deposition of both α-syn and LRRK2 protein aggregates.
Autophagy
Autophagy is the other essential machinery in cells that is responsible for the removal of damaged organelles and large protein aggregates. Various malfunctions of autophagy pathways have been reported in PD, in which both α-syn and LRRK2 are involved. The α-syn A53T mutation seems to interfere with the chaperone-mediated autophagy and macroautophagy pathways in cells, which impairs the clearance of α-syn aggregates. LRRK2 is also implicated in regulating autophagy induction and flux rates in cell cultures. In particular, loss of LRRK2 leads to excessive accumulation of marker proteins involved in the induction of autophagy in cells from the kidney and lung. However, no overt impairment of the autophagy pathway is observed in LRRK2-deficient neurons. Nonetheless, future studies may focus on identifying the molecular partners of LRRK2 in the autophagy pathway in order to fully understand the contribution of LRRK2 in this fundamental cellular process.
Source...