Please use this identifier to cite or link to this item: http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/9408
Title: Age-dependent dynamics of neuronal VAPBALS inclusions in the adult brain
Authors: THULASIDHARAN, APARNA
GARG, LOVLEEN
TENDULKAR, SHWETA
RATNAPARKHI, GIRISH S.
Dept. of Biology
Keywords: Valosin
Autophagy
ALS8
p97
Neuroaggregate
Ageing
FAF1
ALS14
TER94
VCP
2024
Issue Date: Jun-2024
Publisher: Elsevier B.V.
Citation: Neurobiology of Disease, 196, 106517.
Abstract: 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 (VAPP58S) to understand the modulation of these inclusions in the ageing adult brain. The adult VAPP58S fly shows progressive deterioration in motor function till its demise 25 days post-eclosion. The density of VAPP58S-positive brain inclusions is stable for 5–15 days of age. In contrast, adding a single copy of VAPWT to the VAPP58S 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 VAPP58S punctae density, while its knockdown led to enhanced clearance. Expression of a dominant positive allele, TER94R152H, further stabilised VAPP58S 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.
URI: https://doi.org/10.1016/j.nbd.2024.106517
http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/9408
ISSN: 1095-953X
0969-9961
Appears in Collections:JOURNAL ARTICLES

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