Parkinson＇s disease（PD）is the second most common neurodegenerative disease after Alzheimer＇s disease.The etiology of PD is still not completely understood,but the degeneration of dopaminergic（DA）neurons in the s...Parkinson＇s disease（PD）is the second most common neurodegenerative disease after Alzheimer＇s disease.The etiology of PD is still not completely understood,but the degeneration of dopaminergic（DA）neurons in the substantia nigra pars compacta（SNpc）,loss of DA innervation of the striatum,and protein aggregates in the form of Lewy bodies and neurites are its established hallmarks. In addition to α-synuclein accumu- lation in Lewy bodies and neurites, genetic mutations in the genes encoding parkin, PINK, DJ-1, LRRK2 and other proteins are associated with the inherited form of PD. An association study linked also the receptor tyrosine kinase Ret to PD （Meka et al., 2015）. Currently there are only symptomatic treatments available for PD but no cure. Consequently much effort is being made to find neurotrophic and other factors able to stimulate SNpc DA neuron protection and regeneration.展开更多
The neurotrophic signaling of glial cell line-derived neurotrophic factor(GDNF)with its canonical receptor,the receptor tyrosine kinase RET,coupled together with the GDNF family receptor alpha 1 is important for dopam...The neurotrophic signaling of glial cell line-derived neurotrophic factor(GDNF)with its canonical receptor,the receptor tyrosine kinase RET,coupled together with the GDNF family receptor alpha 1 is important for dopaminergic neuron survival and physiology in cell culture experiments and animal models.This prompted the idea to try GDNF/RET signaling as a therapeutic approach to treat Parkinson’s disease with the hallmark of dopaminergic cell death in the substantia nigra of the midbrain.Despite several clinical trials with GDNF in Parkinson’s disease patients,which mainly focused on optimizing the GDNF delivery technique,benefits were only seen in a few patients.In general,the endpoints did not show significant improvements.This suggests that it will be helpful to learn more about the basic biology of this fascinating but complicated GDNF/RET signaling system in the dopaminergic midbrain and about recent developments in the field to facilitate its use in the clinic.Here we will refer to the latest publications and point out important open questions in the field.展开更多
基金supported by grants from the DFG (KR 3529/4-1 to ERK)the town of Hamburg (Lexi to ERK)
文摘Parkinson＇s disease（PD）is the second most common neurodegenerative disease after Alzheimer＇s disease.The etiology of PD is still not completely understood,but the degeneration of dopaminergic（DA）neurons in the substantia nigra pars compacta（SNpc）,loss of DA innervation of the striatum,and protein aggregates in the form of Lewy bodies and neurites are its established hallmarks. In addition to α-synuclein accumu- lation in Lewy bodies and neurites, genetic mutations in the genes encoding parkin, PINK, DJ-1, LRRK2 and other proteins are associated with the inherited form of PD. An association study linked also the receptor tyrosine kinase Ret to PD （Meka et al., 2015）. Currently there are only symptomatic treatments available for PD but no cure. Consequently much effort is being made to find neurotrophic and other factors able to stimulate SNpc DA neuron protection and regeneration.
基金BRACE-Dementia Research,UK(ERK)Alzheimer’s Research UKthe Northcott Devon Medical Foundation(to JAC and ERK)for financial support。
文摘The neurotrophic signaling of glial cell line-derived neurotrophic factor(GDNF)with its canonical receptor,the receptor tyrosine kinase RET,coupled together with the GDNF family receptor alpha 1 is important for dopaminergic neuron survival and physiology in cell culture experiments and animal models.This prompted the idea to try GDNF/RET signaling as a therapeutic approach to treat Parkinson’s disease with the hallmark of dopaminergic cell death in the substantia nigra of the midbrain.Despite several clinical trials with GDNF in Parkinson’s disease patients,which mainly focused on optimizing the GDNF delivery technique,benefits were only seen in a few patients.In general,the endpoints did not show significant improvements.This suggests that it will be helpful to learn more about the basic biology of this fascinating but complicated GDNF/RET signaling system in the dopaminergic midbrain and about recent developments in the field to facilitate its use in the clinic.Here we will refer to the latest publications and point out important open questions in the field.
