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.
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) harbouring 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.
Modeling Motor Neuron Resilience in ALS Using Stem Cells.
Allodi I, Nijssen J, Benitez JA, Schweingruber C, Fuchs A, Bonvicini G, et al
Stem Cell Reports 2019 06;12(6):1329-1341
Axon-Seq Decodes the Motor Axon Transcriptome and Its Modulation in Response to ALS.
Nijssen J, Aguila J, Hoogstraaten R, Kee N, Hedlund E
Stem Cell Reports 2018 Dec;11(6):1565-1578
Single-cell RNA sequencing: Technical advancements and biological applications.
Hedlund E, Deng Q
Mol. Aspects Med. 2018 02;59():36-46
Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis.
Nijssen J, Comley LH, Hedlund E
Acta Neuropathol. 2017 06;133(6):863-885
Laser capture microscopy coupled with Smart-seq2 for precise spatial transcriptomic profiling.
Nichterwitz S, Chen G, Aguila Benitez J, Yilmaz M, Storvall H, Cao M, et al
Nat Commun 2016 07;7():12139
Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS.
Allodi I, Comley L, Nichterwitz S, Nizzardo M, Simone C, Benitez JA, et al
Sci Rep 2016 05;6():25960
Dopamine Receptor Antagonists Enhance Proliferation and Neurogenesis of Midbrain Lmx1a-expressing Progenitors.
Hedlund E, Belnoue L, Theofilopoulos S, Salto C, Bye C, Parish C, et al
Sci Rep 2016 06;6():26448
Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology.
Comley LH, Nijssen J, Frost-Nylen J, Hedlund E
J. Comp. Neurol. 2016 May;524(7):1424-42
Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS.
Comley L, Allodi I, Nichterwitz S, Nizzardo M, Simone C, Corti S, et al
Neuroscience 2015 Apr;291():216-29
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