Neuroprotective activity of ursodeoxycholic acid in CHMP2BIntron5 models of frontotemporal dementia

Ryan J.H West,Chris Ugbode,Laura Fort-Aznar,Sean T Sweeney

doi:10.1016/j.nbd.2020.105047

Ryan J.H West, Chris Ugbode + Show 2 more

Open Access

https://doi.org/10.1016/j.nbd.2020.105047

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Abstract

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 CHMP2BIntron5 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 CHMP2BIntron5. Rescue of CHMP2BIntron5 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.

Highlights

Frontotemporal Dementia (FTD) is a common cause of early-onset dementia, second only to Alzheimer's Disease, with a typical age of onset under 65 years of age
We demonstrate that the administration of Ursodeoxycholic Acid (UDCA) is sufficient to alleviate neuronal aberrations in both Drosophila and mammalian primary neuron models of behavioural variant FTD (bvFTD) associated with the CHMP2BIntron5 mutation
Neither UDCA or Ursocholanic Acid (UCA) had any effect upon neuromuscular junction (NMJ) structure in wild type animals, with no significant variance in bouton number, branch number or NMJ length observed across doses (Fig. 1)

Summary

Introduction

Frontotemporal Dementia (FTD) is a common cause of early-onset dementia, second only to Alzheimer's Disease, with a typical age of onset under 65 years of age. Mutations in TAR DNAbinding protein (TARDBP) (Borroni et al, 2009; Kovacs et al, 2009; Sreedharan et al, 2008; Van Deerlin et al, 2008), Fused in Sarcoma (FUS) (Kwiatkowski Jr. et al, 2009; Vance et al, 2009), C9ORF72 (DeJesus-Hernandez et al, 2011; Gijselinck et al, 2012; Renton et al, 2011), Ubiquilin-2(Deng et al, 2011), p62/sequestosome-1(Fecto et al, 2011;Rubino et al, 2012;Teyssou et al, 2013), Valosin containing Peptide (VCP) (Johnson et al, 2010; Watts et al, 2004) Charged Multivesicular Body protein 2B (CHMP2B) (Parkinson et al, 2006; Skibinski et al, 2005) and more recently TANK Binding Kinase 1 (TBK1) (Freischmidt et al, 2015;Pottier et al, 2015) can be causative for ALS or FTD, or give rise to a disease that has clinical characteristics of both conditions in the same individual (Ling et al, 2013) This genetic and pathological continuum suggests common or partially shared disease mechanisms for this class of FTD-ALS

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