Rôle de Lmx1a et de Lmx1b dans la maintenance des circuits dopaminergiques chez la souris adulte
|Abstract:||The LIM-homeodomain transcription factors Lmx1a and Lmx1b play critical roles during the embryonic development of midbrain dopaminergic progenitors, but their functions in the adult brain remain poorly understood. We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons. Strikingly, conditional inactivation of Lmx1a and Lmx1b in postmitotic dopaminergic neurons recreates some of the early cellular features observed in Parkinson’s disease. We found that Lmx1a/b control expression of key genes involved in mitochondrial functions and their ablation results in impaired respiratory chain activity, increased oxidative stress and mitochondrial DNA damage. Postnatal Lmx1a/b deficiency caused axonal pathology characterized by the presence of alpha-synuclein positive inclusions, followed by a progressive loss of SNpc and VTA dopaminergic neurons. These results reveal the key role of these transcription factors beyond early developmental stages and provide mechanistic links between impaired mitochondrial functions, alpha-synuclein aggregation and long-term survival of dopaminergic neurons. The results also suggest the possibility that disturbed function of Lmx1a and Lmx1b contributes to Parkinson’s disease pathophysiology.|
|Document Type:||Mémoire de maîtrise|
|Open Access Date:||24 April 2018|
|Collection:||Thèses et mémoires|
All documents in CorpusUL are protected by Copyright Act of Canada.