FightAging!
4-16-17

The prospect of replacing lost neurons is one of the major themes of research into Parkinson's disease. The most evident symptoms of this neurodegenerative condition, the tremors and loss of control, are caused by the progressive loss of a small but critical population of dopamine-generating neurons in the brain. This is actually a problem that occurs to all of us to some degree as we age, but Parkinson's patients have either a genetic or environmental vulnerability that makes them less resistant to the underlying processes that drive damage and cell death. As is the case for most neurodegenerative conditions, once you move past the proximate cause of dying cells, the list of mechanisms involved at lower levels in the chain of cause and effect starts to include all of the usual suspects: mitochondrial function; cellular maintenance processes; accumulations of misfolded proteins and other forms of metabolic waste; and so forth.

With the blossoming of the stem cell research community over the past twenty years, replacing lost neurons and their contribution to the functioning of the brain has seemed like a possible short-cut past the difficult question of why exactly it is that these particular neurons are dying. That it is in fact a short cut may or may not be the case, however. Certainly, the root causes of Parkinson's disease are still operating even following a hypothetical safe and reliable replacement of neurons, and it is an open question as to how long they will take to chew through those replacement neurons. Further, actually replacing dopamine-generating neurons safely and reliably has turned out to be a more challenging process than hoped. This is often the case in any field of medical research - even the goals that are easy to explain and visualize, and enjoy widespread support, are long roads. Still, the materials below note one of a number of promising results in neuron replacement that have arrived in recent years. The researchers used cellular reprogramming methods to generate patient-matched neurons from existing support cells in the brain, and went on to show positive results in mice engineered to exhibit Parkinson's symptoms.

Mighty morphed brain cells cure Parkinson's in mice, but human trials still far off

Mice that walk straight and fluidly don't usually make scientists exult, but these did: The lab rodents all had a mouse version of Parkinson's disease and only weeks before had barely been able to lurch and shuffle around their cages. Using a trick from stem cell science, researchers managed to restore the kind of brain cells whose death causes Parkinson's. And the mice walked almost normally. The same technique turned human brain cells, growing in a lab dish, into the dopamine-producing neurons that are AWOL in Parkinson's. Success in lab mice and human cells is many difficult steps away from success in patients. The study nevertheless injected new life into a promising approach to Parkinson's that has suffered setback after setback - replacing the dopamine neurons that are lost in the disease, crippling movement and eventually impairing mental function.

There is no cure for Parkinson's. Drugs that enable the brain to make dopamine help only somewhat, often causing movement abnormalities called dyskinesia as well as other side effects. Rather than replacing the missing dopamine, scientists tried to replace dopamine neurons - but not in the way that researchers have been trying since the late 1980s. In that approach, scientists obtained tissue containing dopamine neurons from first-trimester aborted fetuses and implanted it into patients' brains. Instead, several labs have used stem cells to produce dopamine neurons in dishes. Transplanted into the brains of lab rats with Parkinson's, the neurons reduced rigidity, tremor, and other symptoms. Human studies are expected to begin in the US and Japan this year or next.

Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model

Cell replacement therapies for neurodegenerative disease have focused on transplantation of the cell types affected by the pathological process. Here we describe an alternative strategy for Parkinson's disease in which dopamine neurons are generated by direct conversion of astrocytes. Using three transcription factors, NEUROD1, ASCL1 and LMX1A, and the microRNA miR218, collectively designated NeAL218, we reprogram human astrocytes in vitro, and mouse astrocytes in vivo, into induced dopamine neurons (iDANs). Reprogramming efficiency in vitro is improved by small molecules that promote chromatin remodeling and activate the TGFβ, Shh and Wnt signaling pathways. The reprogramming efficiency of human astrocytes reaches up to 16%, resulting in iDANs with appropriate midbrain markers and excitability.

In a mouse model of Parkinson's disease, NeAL218 alone reprograms adult striatal astrocytes into iDANs that are excitable and correct some aspects of motor behavior in vivo, including gait impairments. With further optimization, this approach may enable clinical therapies for Parkinson's disease by delivery of genes rather than cells.