Neuroprotective activity of ursodeoxycholic acid in CHMP2B models of frontotemporal dementia

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 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.

Astrocytic Reactivity Triggered by defective Mitophagy Activates NF-kB Signaling and Causes Neurotoxicity in Frontotemporal Dementia Type 3

“…On the contrary when treated with 100nM or 500nM of UDCA, we observed elevated ROS levels causing cell death (data not shown). Overall our data demonstrate that UDCA acts as an antioxidant in CHMP2B astrocytes when applied at low dose concentrations, similar to the effects observed in drosophila CHMP2B Intron5 models of FTD [64].…”

“…Ursodeoxycholic Acid (UDCA) has been proven to rescue apoptotic cascades downstream of autophagic and endosomal perturbations in CHMP2B Intron5 expressing Drosophila [64]. In addition it has proven to rescue mitochondrial defects in parkin-deficient neurons in iPSC derived models [65].…”

Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3

“…The evidence of mitochondria dysfunction is further supported by our RNA-seq data showing downregulation of additional mitochondrial-related genes in FTD3 astrocytes ( Figure 3 L; Table S2 ). Ursodeoxycholic acid (UDCA) has been proved to rescue apoptotic cascades downstream of autophagic and endosomal perturbations in CHMP2B Intron5 expressing Drosophila ( West et al., 2020 ). In addition, it has proved to rescue mitochondrial defects in parkin -deficient neurons in iPSC-derived models ( Mortiboys et al., 2013 ).…”

Regulated cell death: discovery, features and implications for neurodegenerative diseases

“…The focus of anti-apoptosis is the mitochondrial damage of injured motor neurons and the abnormal calcium treatment leading to the apoptotic cascade. Two studies with preliminary reports on the use of Ursodeoxycholic acid and Tauroursodeoxycholic acid have moderately positive prospects [ 312 , 313 ]. Studies have shown that the neuroinflammatory process related to reactive astrocytes and microglia plays an important role in ALS neurodegeneration [ 314 , 315 ].…”