For ALS, SOD transgenic models lacking CCS demonstrate that aberrant activities dependent on copperloaded SOD are unlikely to be the pathogenic mechanism.Themouse modelsh ave notonlyprov id ed subst anti alprogress in understanding the molecular Riboflavin mechanisms of neurodegeneration, they are also instrumental in identifying targets for mechanismbased therapeutics, such as BACE.These genetically engineered models are valuable for testing a variety of therapeutic app roaches, inc lud ing A immuno therapy in AD, creat ine in ALS, and sod ium buty rate in SMA. In summar y, investigation of the pathogeneses of neurodegenerative diseases using transgenic models and other approaches has made spectacular progress over the past few years, and we anticipate that more promising therapies based on our present understanding of the disease mechanisms will continue to be identified.Transgenic models should prov ide a highly useful tool for quickly assessing which therapies should be pursued.Supported by grants from the U.RECEIVED JANUARY; ACCEPTED MAY. Nature. Science. Science. Nature. Science. Nature. Science. Nature. Nature. Nature. Science. Nature. Nature. Nature. Nature. Nature. Nature. Nature. Science. Neuron. Neurobiology. Science. Science. Nature. Proc. Natl. Acad. Sci. USA. nature neuroscience volume no july View publication stats View publication stats These findings raise hope for the development of stem cell therapies in human neurodegenerative disorders.Before clinical trials are initiated, we need to know much more about how to control stem cell Calcitriol proliferation and differentiation into specific phenotypes, induce their integration into existing neural and synaptic circuits, and optimize functional recovery in animal models closely resembling the human disease.Stem cells are immature cellswith prolonged selfrenewal capacity and, depending on their or ig in, ability to differentiate into multiple cell types or all cells of the body.Transplantation of stem cells or their der ivatives, and mobilization of endogenous stem cellswithin the adult brain, have been proposed as future therapies for neurodegenerative diseases.It may seem unrealistic, though, to induce functional recoveryby replacing cells lost through disease, consider ing the complexity of human brain structure and function.Studies in animal models have never theless demonstrated that neuronal replacement and par tial reconstruction of damaged neuronal circuitryis possible.There is also ev idence from clinical tr ials that cell replacement in the diseased human brain can lead to symptomatic relief.In each of these neurodegenerative diseases, a different spectrum of cell types is affected; therefore, different types of neurons are required for replacement.We argue that longterm surv ival of new, functionally integrated neurons is the main goal to achieve maximum symptomatic relief through stem cell therapy.Studies in patients with PD after intrastriatal transplantation of human fetal mesencephalic tissue, rich in postmitotic dopaminergic neurons, have provided proof of principle that neuronal replacement can work in the human brain.The grafted neurons survive and reinnervate the striatum for as long as years despite an ongoing disease process, which destroys the patients own dopaminergic neurons. The grafts are able to normalize striatal dopamine release and to reverse the impairment of cortical activation underlying AKINESIA.Thus, grafted dopaminergic neurons can become functionally integrated into neuronal circuitries in the brain.Several openlabel trials have reported clinical benefit.