TY  - JOUR
AU  - Voelkl, Kerstin
AU  - Gutiérrez-Ángel, Sara
AU  - Keeling, Sophie
AU  - Koyuncu, Seda
AU  - da Silva Padilha, Miguel
AU  - Feigenbutz, Dennis
AU  - Arzberger, Thomas
AU  - Vilchez, David
AU  - Klein, Rüdiger
AU  - Dudanova, Irina
TI  - Neuroprotective effects of hepatoma-derived growth factor in models of Huntington's disease.
JO  - Life science alliance
VL  - 6
IS  - 11
SN  - 2575-1077
CY  - Heidelberg
PB  - EMBO Press
M1  - DZNE-2023-00799
SP  - e202302018
PY  - 2023
AB  - 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.
KW  - Mice
KW  - Humans
KW  - Animals
KW  - Huntington Disease: genetics
KW  - Huntington Disease: drug therapy
KW  - Huntington Disease: metabolism
KW  - Neuroprotective Agents: pharmacology
KW  - Neuroprotective Agents: metabolism
KW  - Neuroprotective Agents: therapeutic use
KW  - Neurons: metabolism
KW  - Intercellular Signaling Peptides and Proteins: metabolism
KW  - Neuroprotective Agents (NLM Chemicals)
KW  - hepatoma-derived growth factor (NLM Chemicals)
KW  - Intercellular Signaling Peptides and Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10427761
C6  - pmid:37580082
DO  - DOI:10.26508/lsa.202302018
UR  - https://pub.dzne.de/record/259914
ER  -