LMX1B is a transcription factor that plays an essential role in the development of dopaminergic neurons. We have recently described a new role for LMX1B in dopaminergic neurons as a regulator of the autophagic-lysosomal degradation pathway (regulated breakdown of cellular materials), and we have shown that its dysfunction results in abnormalities resembling the early cellular abnormalities seen in Parkinson's disease (PD). In addition, LMX1B expression is reduced in post-mortem brain tissue from those who had PD and polymorphisms in the LMX1B gene have been associated with PD. These findings suggest that LMX1B dysfunction could be associated with the autophagy alterations described in PD.
Our hypothesis is that LMX1B is a potential target for neuroprotective therapies. We propose that increased expression/activity of LMX1B might have neuroprotective effects by restoring the autophagic function that is altered in PD pre-clinical models and in the age-related accumulation and aggregation of disordered proteins like alpha-synuclein.
This project is a proof-of-concept study where we will evaluate overexpression of LMX1B in the substantia nigra (brain region; SN) by injecting a viral vector and will evaluate effects on the survival and function of dopamine neurons in a PD pre-clinical model where neurodegeneration is induced through a neurotoxin. In addition, we will further investigate LMX1B expression levels and distribution patterns in postmortem brain tissue. We also will determine its expression in the SN of healthy cases, as well as study its expression in different brain regions of idiopathic (no known cause) PD cases.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Our results will clarify the potential of LMX1B as a neuroprotective target for future development of therapeutic strategies directed to maintain sustained expression and/or activity of LMX1B and will contribute to the maintenance of cellular dopamine function in the context of Parkinson's.
Next Steps for Development:
The development of future therapeutic strategies for clinical application should be directed toward the maintenance of sustained expression and activity of LMX1B. This could be achieved either by delivery of the LMX1B gene or by pharmacological manipulation of its expression/activity in dopamine neurons.