The lethal motor neuron diseases (MNDs) amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are defined by the loss of somatic motor neurons that innervate muscles in arms, legs, trunk and face, leading to muscle wasting. However, not all motor neurons are equally vulnerable; certain groups of motor neurons are spared, including those in the oculomotor nucleus, controlling eye movement and motor neurons in the Onuf's nucleus, controlling pelvic muscles. The reasons for the differential vulnerability to degeneration among motor neuron groups are unknown.
Research in the Hedlund lab is aimed at elucidating mechanisms of neuronal vulnerability and resistance with the goal of identifying new molecular targets for the treatment of motor neuron diseases.
Towards this goal, we utilize laser capture microdissection coupled with RNA sequencing to dissect molecular pathways in distinct motor neuron populations in animal models of MNDs. We also perform cross-disease analyses of degenerative and regenerative axonal responses at neuromuscular junctions - the specialized synapses between motor neurons and muscle.
Motor neuron cultures derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) harboring disease-inducing mutations are coupled with microfluidics to model MNDs and study neuronal vulnerability and protection in vitro. Finally, we modulate candidate gene expression in vivo in transgenic MND mouse models to induce motor neuron protection and axonal regeneration.
Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS.
Sci Rep 2016 May;6():25960
Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology.
J. Comp. Neurol. 2016 May;524(7):1424-42
Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS.
Neuroscience 2015 Apr;291():216-29
Presymptomatic activation of the PDGF-CC pathway accelerates onset of ALS neurodegeneration.
Acta Neuropathol. 2016 Mar;131(3):453-64
Selection Based on FOXA2 Expression Is Not Sufficient to Enrich for Dopamine Neurons From Human Pluripotent Stem Cells.
Stem Cells Transl Med 2014 Sep;3(9):1032-42
Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis.
Cell. Mol. Life Sci. 2014 Mar;71(6):999-1015
Specific and integrated roles of Lmx1a, Lmx1b and Phox2a in ventral midbrain development.
Development 2011 Aug;138(16):3399-408
Transcription factor-induced lineage selection of stem-cell-derived neural progenitor cells.
Cell Stem Cell 2011 Jun;8(6):663-75