Journal Article

DZNE-2023-00799

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Neuroprotective effects of hepatoma-derived growth factor in models of Huntington's disease.

Voelkl, K. ; Gutiérrez-Ángel, S. ; Keeling, S. ; Koyuncu, S. ; da Silva Padilha, M. ; Feigenbutz, D. ; Arzberger, T.DZNE* ; Vilchez, D. ; Klein, R. ; Dudanova, I.

2023
EMBO Press Heidelberg

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Please use a persistent id in citations: doi:10.26508/lsa.202302018

Abstract: Huntington's disease (HD) is a movement disorder caused by a mutation in the Huntingtin gene that leads to severe neurodegeneration. Molecular mechanisms of HD are not sufficiently understood, and no cure is currently available. Here, we demonstrate neuroprotective effects of hepatoma-derived growth factor (HDGF) in cellular and mouse HD models. We show that HD-vulnerable neurons in the striatum and cortex express lower levels of HDGF than resistant ones. Moreover, lack of endogenous HDGF exacerbated motor impairments and reduced the life span of R6/2 Huntington's disease mice. AAV-mediated delivery of HDGF into the brain reduced mutant Huntingtin inclusion load, but had no significant effect on motor behavior or life span. Interestingly, both nuclear and cytoplasmic versions of HDGF were efficient in rescuing mutant Huntingtin toxicity in cellular HD models. Moreover, extracellular application of recombinant HDGF improved viability of mutant Huntingtin-expressing primary neurons and reduced mutant Huntingtin aggregation in neural progenitor cells differentiated from human patient-derived induced pluripotent stem cells. Our findings provide new insights into the pathomechanisms of HD and demonstrate neuroprotective potential of HDGF in neurodegeneration.

Keyword(s): Mice (MeSH) ; Humans (MeSH) ; Animals (MeSH) ; Huntington Disease: genetics (MeSH) ; Huntington Disease: drug therapy (MeSH) ; Huntington Disease: metabolism (MeSH) ; Neuroprotective Agents: pharmacology (MeSH) ; Neuroprotective Agents: metabolism (MeSH) ; Neuroprotective Agents: therapeutic use (MeSH) ; Neurons: metabolism (MeSH) ; Intercellular Signaling Peptides and Proteins: metabolism (MeSH) ; Neuroprotective Agents ; hepatoma-derived growth factor ; Intercellular Signaling Peptides and Proteins

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Contributing Institute(s):

1. Neuropathology / Brainbank (Neuropathology / Brainbank)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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