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Protective effect of neuronal chaperone-mediated autophagy against brain aging and disease-driven neuroproteotoxicity

ABSTRACT: Components of the proteostasis network malfunction in the aging brain and this reduced neuronal protein quality control has been proposed to increase risk for neurodegeneration. Here, we have focused on chaperone-mediated autophagy (CMA), a selective type of autophagy that contributes to turnover of neurodegeneration-related proteins. We generated mouse models with CMA blockage in dopaminergic or glutamatergic neurons to investigate the physiological role of CMA in neurons in vivo and the consequences of neuronal CMA loss in aging, We found that loss of neuronal CMA leads to behavioral impairments, altered neuronal function, selective changes in the neuronal proteome and proteotoxicity, all reminiscent of brain aging. Furthermore, imposing CMA loss on an experimental mouse model of Alzheimer’s disease, increased neuronal disease vulnerability and accelerated disease progression. We conclude that functional CMA is essential for neuronal proteostasis and that CMA activation could be an efficient disease-modifying therapy in neurodegenerative disorders.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Danielle Swaney

LAB HEAD: Danielle Swaney

PROVIDER: PXD017108 | Pride | 2021-04-23

REPOSITORIES: Pride

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Project description:Protein function is controlled by the cellular proteostasis network. Proteostasis is energetically costly and those costs must be balanced with the energy needs of other physiological functions. Hypertonic stress causes widespread protein damage in C. elegans. Suppression and management of protein damage is essential for optimal survival under hypertonic conditions. ASH chemosensory neurons allow C. elegans to detect and avoid strongly hypertonic environments. We demonstrate that gene mutations that disrupt ASH mediated hypertonic avoidance behavior or genetic ablation of ASH neurons enhance survival during hypertonic stress. Enhanced survival is not due to altered systemic volume homeostasis or organic osmolyte accumulation. Instead, loss of ASH neuron function reduces protein damage in non-neuronal cells. Improved proteostasis capacity is due in part to upregulation of genes that play important roles in managing protein damage. We propose that inhibitory signaling from ASH neurons normally suppresses expression of genes required for non-neuronal cell proteostasis. Because all cells have the capacity to sense and respond to stressors, inhibitory neuronal signaling may be important for minimizing activation of cellular stress resistance and proteostasis pathways during short duration and less extreme stressors or stressors that can be avoided by behavioral changes. Neuronal regulation of systemic proteostasis allows the nervous system to monitor environmental variables and more effectively partition finite energy resources between different organismal processes. Our studies add to a growing body of work demonstrating that intercellular communication between neuronal and non-neuronal cells plays a critical role in integrating cellular stress resistance with other organismal physiological demands and associated energy costs. mRNA expression profiling of synchronized L4 stage wild-type N2 Bristol and VC1262 osm-9(ok1677) C. elegans strains under control (51mM NaCl) and hypertonic stress (200mM NaCl).

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Protective effect of neuronal chaperone-mediated autophagy against brain aging and disease-driven neuroproteotoxicity

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