Hedlund Laboratory

Research focus

Neurodegenerative diseases are characterized by the selective loss of specific neuronal populations with corresponding distinct clinical features, even when the pathogenic proteins are ubiquitously expressed. 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 and trochlear nuclei, 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. The underlying causes of ALS and SMA appear quite distinct, but the similar pattern of motor neuron degeneration and sparing indicate that these diseases could share degenerative and protective pathways, independent of their distinct etiologies. Investigating cell intrinsic pathways that are differentially activated within resistant and vulnerable motor neurons could reveal mechanisms of selective neuronal degeneration and lead to therapies preventing progressive motor neuron loss.

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 MNDs. 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.