Age-dependent dynamics of neuronal VAPB ^ALS inclusions in the adult brain.

Publisher: Academic Press Country of Publication: United States NLM ID: 9500169 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-953X (Electronic) Linking ISSN: 09699961 NLM ISO Abbreviation: Neurobiol Dis Subsets: MEDLINE

Publication: San Diego, CA : Academic Press
Original Publication: Oxford : Blackwell Science, c1994-

Aging*/metabolism ; Aging*/pathology ; Aging*/physiology ; Amyotrophic Lateral Sclerosis*/metabolism ; Amyotrophic Lateral Sclerosis*/pathology ; Amyotrophic Lateral Sclerosis*/genetics ; Brain*/metabolism ; Brain*/pathology ; Drosophila Proteins*/metabolism ; Drosophila Proteins*/genetics ; Inclusion Bodies*/metabolism ; Inclusion Bodies*/pathology; Animals ; Animals, Genetically Modified ; Autophagy/physiology ; Disease Models, Animal ; Drosophila ; Neurons/metabolism ; Neurons/pathology ; Valosin Containing Protein/metabolism ; Valosin Containing Protein/genetics

Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive and fatal disease, caused by the degeneration of upper and lower motor neurons within the brain and spinal cord in the ageing human. The dying neurons contain cytoplasmic inclusions linked to the onset and progression of the disease. Here, we use a Drosophila model of ALS8 (VAP ^P58S ) to understand the modulation of these inclusions in the ageing adult brain. The adult VAP ^P58S fly shows progressive deterioration in motor function till its demise 25 days post-eclosion. The density of VAP ^P58S -positive brain inclusions is stable for 5-15 days of age. In contrast, adding a single copy of VAP ^WT to the VAP ^P58S animal leads to a large decrease in inclusion density with concomitant rescue of motor function and lifespan. ER stress, a contributing factor in disease, shows reduction with ageing for the disease model. Autophagy, rather than the Ubiquitin Proteasome system, is the dominant mechanism for aggregate clearance. We explored the ability of Drosophila Valosin-containing protein (VCP/TER94), the ALS14 locus, which is involved in cellular protein clearance, to regulate age-dependent aggregation. Contrary to expectation, TER94 overexpression increased VAP ^P58S punctae density, while its knockdown led to enhanced clearance. Expression of a dominant positive allele, TER94 ^R152H , further stabilised VAP ^P58S puncta, cementing roles for an ALS8-ALS14 axis. Our results are explained by a mechanism where autophagy is modulated by TER94 knockdown. Our study sheds light on the complex regulatory events involved in the neuronal maintenance of ALS8 aggregates, suggesting a context-dependent switch between proteasomal and autophagy-based mechanisms as the larvae develop into an adult. A deeper understanding of the nucleation and clearance of the inclusions, which affect cellular stress and function, is essential for understanding the initiation and progression of ALS.
(Copyright © 2024. Published by Elsevier Inc.)

Keywords: ALS14; ALS8; Ageing; Autophagy; FAF1; Neuroaggregate; TER94; VCP; Valosin; p97

0 (Drosophila Proteins)
EC 3.6.4.6 (Valosin Containing Protein)
0 (Vap33 protein, Drosophila)

Amyotrophic Lateral Sclerosis 8

Date Created: 20240428 Date Completed: 20240518 Latest Revision: 20240524

20240524

10.1016/j.nbd.2024.106517

38679111