Proteostasis and neurodegeneration: a closer look at autophagy in Alzheimer's disease

Barmaki, Haleh; Nourazarian, Alireza; Khaki-Khatibi, Fatemeh

doi:10.3389/fnagi.2023.1281338

Cited by 12 publications

(2 citation statements)

References 127 publications

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“…Numerous studies have implicated changes in specific molecular processes and pathways with AD, including mitochondrial function 100–103 , lipid biosynthesis 104–106 , proteostasis 107–109 , intracellular trafficking 110–112 , inflammation 113–115 , and more. To study the dysregulation of these processes by disease in a supertype-specific fashion, we tested for gene expression changes along CPS across each of the 139 supertypes ( Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

Integrated multimodal cell atlas of Alzheimer’s disease

Gabitto,

Travaglini,

Rachleff

et al. 2023

Preprint

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Alzheimer’s disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research atSEA-AD.org.

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Section: Resultsmentioning

confidence: 99%

Integrated multimodal cell atlas of Alzheimer’s disease

Gabitto,

Travaglini,

Rachleff

et al. 2023

Preprint

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“…Autophagy can selectively target specific protein aggregates or damaged organelles, contributing to the maintenance of cellular proteostasis (Barmaki et al., 2023). Understanding the intricate interplay between autophagy and proteostasis is crucial for developing therapeutic strategies to combat various protein misfolding and aggregation diseases.…”

Section: Classification Of Autophagymentioning

confidence: 99%

Role of autophagy and proteostasis in neurodegenerative diseases: Exploring the therapeutic interventions

Panwar,

Uniyal,

Kukreti

et al. 2024

Chem Biol Drug Des

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Neurodegenerative disorders are devastating disorders characterized by gradual loss of neurons and cognition or mobility impairment. The common pathological features of these diseases are associated with the accumulation of misfolded or aggregation of proteins. The pivotal roles of autophagy and proteostasis in maintaining cellular health and preventing the accumulation of misfolded proteins, which are associated with neurodegenerative diseases like Huntington's disease (HD), Alzheimer's disease (AD), and Parkinson's disease (PD). This article presents an in‐depth examination of the interplay between autophagy and proteostasis, highlighting how these processes cooperatively contribute to cellular homeostasis and prevent pathogenic protein aggregate accumulation. Furthermore, the review emphasises the potential therapeutic implications of targeting autophagy and proteostasis to mitigate neurodegenerative diseases. While advancements in research hold promise for developing novel treatments, the article also addresses the challenges and complexities associated with modulating these intricate cellular pathways. Ultimately, advancing understanding of the underlying mechanism of autophagy and proteostasis in neurodegenerative disorders provides valuable insights into potential therapeutic avenues and future research directions.

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