Eva Hedlund's research

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.

Microscopic image of motor neurons in blue and yellow.
Motor neurons derived from human induced pluripotent stem cells. Photo: Jik Nijssen

Neurodegenerative diseases are characterized by the selective loss of specific neuronal populations with corresponding distinct clinical features. Why specific neuron types are selectively vulnerable to a neurodegenerative disease process, such as motor neurons in amyotrophic lateral sclerosis (ALS) or dopamine neurons in Parkinson’s disease (PD), is currently unclear. It is particularly intriguing as disease-causative genes are often broadly expressed in the nervous system and sometimes even in every cell in our body.

We are focused on understanding mechanisms of selective neuronal vulnerability and resilience seen in neurodegenerative diseases, with particular emphasis on the lethal motor neuron disease ALS. We believe that investigating cell intrinsic properties of neurons that show either extreme vulnerability or particular resilience and even regenerative properties in response to disease could reveal mechanisms that can be targeted by gene therapy approaches to render neurons more resistant.

Towards this purpose we have developed a method (LCM-seq) that allows for spatial RNA sequencing at the single cell level of partially degraded human tissues with exceptional sensitivity and gene detection. We are now using LCM-seq to unravel motor neuron diversity in the human spinal cord as well as to deduce the response of individual neuron to disease as these are either degenerating, persisting or regenerating in response to ALS.

Microscopic image of motor axons in  green and red.
Human motor axons grown in isolation using microfluidic devices (stained against βIII-tubulin (green) and Tau (red)). Photo: Jik Nijssen

In several neurodegenerative diseases, it is the long neuronal processes (axons) and their synapses (with other neurons or muscle) that first show signs of pathology and degenerate. Still, these axonal processes are often overlooked. Towards the goal of understanding early disease processes in axons and identify targets for disease intervention, we have developed a highly robust method (Axon-seq) to sequence the content of axons and to analyze disease-induced dysregulation of the axonal mRNA content

We are now utilizing Axon-seq to increase the understanding of axon biology in general and to unravel early disease mechanisms in ALS using neurons specified from human induced pluripotent stem cells where we have introduced disease-causing mutations using CRISPR-Cas9 genome editing.

    Selected publications

    LCM-seq reveals unique transcriptional adaptation mechanisms of resistant neurons and identifies protective pathways in spinal muscular atrophy.
    Nichterwitz S, Nijssen J, Storvall H, Schweingruber C, Comley LH, Allodi I, Lee MV, Deng Q, Sandberg R, Hedlund E
    Genome Res 2020 Aug;30(8):1083-1096

    Synaptotagmin 13 is neuroprotective across motor neuron diseases.
    Nizzardo M, Taiana M, Rizzo F, Aguila Benitez J, Nijssen J, Allodi I, Melzi V, Bresolin N, Comi GP, Hedlund E, Corti S
    Acta Neuropathol 2020 05;139(5):837-853

    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

     

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      Eva Hedlund

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