Neural grafting for Parkinson's disease:challenges and prospects

Parkinson＇s disease（PD） is a neurodegenerative condition which causes a characteristic movement disorder secondary to loss of dopaminergic neurons in the substanitia nigra.The motor disorder responds well to dopamine-replacement therapies,though these result in significant adverse effects due to non-physiological release of dopamine in the striatum,and off-target effects.Cell-based regenerative treatments offer a potential means for targeted replacement of dopamine,in a physiological manner.Dopaminergic neurons for cell-based therapies can be obtained from several sources.Fetal ventral mesencephalon tissue contains dopaminergic neuron progenitors,and has been transplanted into the striatum of PD patients with good results in a number of cases.However,the ethical implications and logistical challenges of using fetal tissue mean that fetal ventral mesencephalon is unlikely to be used in a widespread clinical setting.Induced pluripotent stem cells can be used to generate dopaminergic neurons for transplantation,providing a source of autologous tissue for grafting.This approach means that challenges associated with allografts,such as the potential for immune rejection,can be circumvented.However,the associated cost and difficulty in producing a standardized product from different cell lines means that,at present,this approach is not commercially viable as a cell-based therapy.Dopaminergic neurons derived from embryonic stem cells offer the most promising basis for a cell-based therapy for Parkinson＇s disease,with trials due to commence in the next few years.Though there are ethical considerations to take into account when using embryonic tissue,the possibility of producing a standardized,optimized cell product means that this approach can be both effective,and commercially viable.

Promoting axon regeneration in the central nervous system by increasing PI3-kinase signaling

Much research has focused on the PI3-kinase and PTEN signaling pathway with the aim to stimulate repair of the injured central nervous system.Axons in the central nervous system fail to regenerate,meaning that injuries or diseases that cause loss of axonal connectivity have life-changing consequences.In 2008,genetic deletion of PTEN was identified as a means of stimulating robust regeneration in the optic nerve.PTEN is a phosphatase that opposes the actions of PI3-kinase,a family of enzymes that function to generate the membrane phospholipid PIP_(3) from PIP_(2)(phosphatidylinositol(3,4,5)-trisphosphate from phosphatidylinositol(4,5)-bisphosphate).Deletion of PTEN therefore allows elevated signaling downstream of PI3-kinase,and was initially demonstrated to promote axon regeneration by signaling through mTOR.More recently,additional mechanisms have been identified that contribute to the neuron-intrinsic control of regenerative ability.This review describes neuronal signaling pathways downstream of PI3-kinase and PIP3,and considers them in relation to both developmental and regenerative axon growth.We briefly discuss the key neuron-intrinsic mechanisms that govern regenerative ability,and describe how these are affected by signaling through PI3-kinase.We highlight the recent finding of a developmental decline in the generation of PIP_(3) as a key reason for regenerative failure,and summarize the studies that target an increase in signaling downstream of PI3-kinase to facilitate regeneration in the adult central nervous system.Finally,we discuss obstacles that remain to be overcome in order to generate a robust strategy for repairing the injured central nervous system through manipulation of PI3-kinase signaling.