Neuroprotective activity of ursodeoxycholic acid in CHMP2BIntron5 models of frontotemporal dementia

NEUROBIOLOGY OF DISEASE

卷:144

Article

West, Ryan J. H.^2,3  Ugbode, Chris¹  Fort-Aznar, Laura¹  Sweeney, Sean T.¹ 

[1] Univ York, Dept Biol, York YO10 5DD, N Yorkshire, England

[2] Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield S10 2HQ, S Yorkshire, England

[3] Univ Sheffield, Neurosci Inst, Western Bank, Sheffield S10 2TN, S Yorkshire, England

关键词: Amyotrophic Lateral Sclerosis;    ALS;    CHMP2B;    Frontotemporal dementia;    FTD;    UDCA;    Glutathione;    MND;    Neurodegeneration;   

DOI  :  10.1016/j.nbd.2020.105047

来源: Elsevier

【 摘 要 】

Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. It represents part of the FTD-Amyotrophic Lateral Sclerosis (ALS) spectrum, a continuum of genetically and pathologically overlapping disorders. FTD-causing mutations in CHMP2B, a gene encoding a core component of the heteromeric ESCRT-III Complex, lead to perturbed endosomal-lysosomal and autophagic trafficking with impaired proteostasis. While CHMP2B mutations are rare, dysfunctional endosomal-lysosomal signalling is common across the FTD-ALS spectrum. Using our established Drosophila and mammalian models of CHMP2B(Intron5) induced FTD we demonstrate that the FDA-approved compound Ursodeoxycholic Acid (UDCA) conveys neuroprotection, downstream of endosomal-lysosomal dysfunction in both Drosophila and primary mammalian neurons. UDCA exhibited a dose dependent rescue of neuronal structure and function in Drosophila pan-neuronally expressing CHMP2B(Intron5). Rescue of CHMP2B(Intron5 )dependent dendritic collapse and apoptosis with UDCA in rat primary neurons was also observed. UDCA failed to ameliorate aberrant accumulation of endosomal and autophagic organelles or ubiquitinated neuronal inclusions in both models. We demonstrate the neuroprotective activity of UDCA downstream of endosomal-lysosomal and autophagic dysfunction, delineating the molecular mode of action of UDCA and highlighting its potential as a therapeutic for the treatment of FTD-ALS spectrum disorders.