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Klim, Joseph

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Klim

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Joseph

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Klim, Joseph

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2017 - 20192

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Author's Publications: search.filters.isAuthorOfPublication.069b4f4b-5041-492c-ab52-d0b5747e845f

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    Reactive Astrocytes Promote ALS-like Degeneration and Intracellular Protein Aggregation in Human Motor Neurons by Disrupting Autophagy through TGF-β1
    (Elsevier, 2017) Tripathi, Pratibha; Rodriguez-Muela, Natalia; Klim, Joseph; de Boer, A. Sophie; Agrawal, Sahil; Sandoe, Jackson; Lopes, Claudia S.; Ogliari, Karolyn Sassi; Williams, Luis A.; Shear, Matthew; Rubin, Lee; Eggan, Kevin; Zhou, Qiao
    Summary Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease. Astrocytic factors are known to contribute to motor neuron degeneration and death in ALS. However, the role of astrocyte in promoting motor neuron protein aggregation, a disease hallmark of ALS, remains largely unclear. Here, using culture models of human motor neurons and primary astrocytes of different genotypes (wild-type or SOD1 mutant) and reactive states (non-reactive or reactive), we show that reactive astrocytes, regardless of their genotypes, reduce motor neuron health and lead to moderate neuronal loss. After prolonged co-cultures of up to 2 months, motor neurons show increased axonal and cytoplasmic protein inclusions characteristic of ALS. Reactive astrocytes induce protein aggregation in part by releasing transforming growth factor β1 (TGF-β1), which disrupts motor neuron autophagy through the mTOR pathway. These results reveal the important contribution of reactive astrocytes in promoting aspects of ALS pathology independent of genetic influences.
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    ALS-Implicated Protein TDP-43 Sustains Levels of STMN2, a Mediator of Motor Neuron Growth and Repair
    (Springer Nature, 2019-01-14) Limone, Francesco; Guerra San Juan, Irune; Burberry, Aaron; Kirchner, Rory; Chen, Kuchuan; Eggan, Kevin; Klim, Joseph; Williams, Luis; Davis-Dusenbery, Brandi N; Mordes, Daniel; Steinbaugh, Michael; Gamage, Kanchana; Moccia, Rob; Cassel, Seth; Wainger, Brian; Woolf, Clifford
    The discovery that TDP-43 mutations cause familial ALS and that many patients display pathological TDP-43 mislocalization has nominated altered RNA metabolism as a potential disease mechanism. Despite its importance, the identity of RNAs regulated by TDP-43 in motor neurons remains poorly understood. Here, we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, we found STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown, in patient-specific motor neurons, following TDP-43 mislocalization, and in the postmortem patient spinal cords. Loss of STMN2 upon reduced TDP-43 function was due to the emergence of a cryptic exon, which is of substantial functional importance, as we further demonstrate that STMN2 is necessary for both axonal outgrowth and repair. Importantly, post-translational stabilization of STMN2 could rescue neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose restoring STMN2 expression warrants future examination as an ALS therapeutic strategy.