bims-proned 2023-10-01 papers

Issue of 2023‒10‒01
five papers selected by
Verena Kohler

bioRxiv. 2023 Sep 13. pii: 2023.09.12.556394. [Epub ahead of print]

DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.

Ran-Der Hwang, Yu-Ning Lu, Qing Tang, Goran Periz, Giho Park, Xiangning Li, Yang Liu, Tao Zhang, Jiou Wang.

Proteotoxic stress impairs cellular homeostasis and underlies the pathogeneses of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of the proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in tissues from ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.

DOI: https://doi.org/10.1101/2023.09.12.556394

J Mol Biol. 2023 Sep 21. pii: S0022-2836(23)00396-0. [Epub ahead of print] 168285

An Innate Host Defense Protein; β2-Microglobulin Keeps a Check on α-Synuclein Amyloid Assembly: Implications in Parkinson's disease.

Khushboo Rani, Arumay Pal, Bharat Gurnani, Pratibha Agrawala, Dibyendu K Sasmal, Neha Jain.

Amyloid formation due to protein misfolding has gained significant attention due to its association with neurodegenerative diseases. α-Synuclein (α-syn) is one such protein that undergoes a profound conformational switch to form higher order cross-β-sheet structures, resulting in amyloid formation, which is linked to the pathophysiology of Parkinson's disease (PD). The present status of research on α-syn aggregation and PD reveals that the disease progression may be linked with many other diseases, such as kidney-related disorders. Unraveling the link between PD and non-neurological diseases may help in early detection and a better understanding of PD progression. Herein, we investigated the modulation of α-syn in the presence of β2-microglobulin (β2m), a structural protein associated with dialysis-related amyloidosis. We took a multi-disciplinary approach to establish that β2m mitigates amyloid formation by α-syn. Our fluorescence, microscopy and toxicity data demonstrated that sub-stoichiometric ratio of β2m drives α-syn into off-pathway non-toxic aggregates incompetent of transforming into amyloids. Using AlphaFold2 and all-atom MD simulation, we showed that the β-strand segments (β1 and β2) of α-synuclein, which frequently engage in interactions within amyloid fibrils, interact with the last β-strand at the C-terminal of β2m. The outcome of this study will unravel the yet unknown potential linkage of PD with kidney-related disorders. Insights from the cross-talk between two amyloidogenic proteins will lead to early diagnosis and new therapeutic approaches for treating Parkinson's disease. Finally, disruption of the nucleation process of α-syn amyloids by targeting the β1-β2 region will constitute a potential therapeutic approach for inhibiting amyloid formation.

Keywords: Parkinson's disease; amyloids; chaperone-like proteins; α-synuclein; β(2)-microglobulin

DOI: https://doi.org/10.1016/j.jmb.2023.168285

Neurosci Bull. 2023 Sep 27.

Decoding the Cellular Trafficking of Prion-like Proteins in Neurodegenerative Diseases.

Chenjun Hu, Yiqun Yan, Yanhong Jin, Jun Yang, Yongmei Xi, Zhen Zhong.

The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.

Keywords: Degradation; Endocytosis; Endolyosomal leaking; Neurodegenerative diseases; Prion-like propagation; Seeding

DOI: https://doi.org/10.1007/s12264-023-01115-9

Biology (Basel). 2023 Aug 25. pii: 1169. [Epub ahead of print]12(9):

Role of NFE2L1 in the Regulation of Proteostasis: Implications for Aging and Neurodegenerative Diseases.

Aswathy Chandran, Haley Jane Oliver, Jean-Christophe Rochet.

A hallmark of aging and neurodegenerative diseases is a disruption of proteome homeostasis ("proteostasis") that is caused to a considerable extent by a decrease in the efficiency of protein degradation systems. The ubiquitin proteasome system (UPS) is the major cellular pathway involved in the clearance of small, short-lived proteins, including amyloidogenic proteins that form aggregates in neurodegenerative diseases. Age-dependent decreases in proteasome subunit expression coupled with the inhibition of proteasome function by aggregated UPS substrates result in a feedforward loop that accelerates disease progression. Nuclear factor erythroid 2- like 1 (NFE2L1) is a transcription factor primarily responsible for the proteasome inhibitor-induced "bounce-back effect" regulating the expression of proteasome subunits. NFE2L1 is localized to the endoplasmic reticulum (ER), where it is rapidly degraded under basal conditions by the ER-associated degradation (ERAD) pathway. Under conditions leading to proteasome impairment, NFE2L1 is cleaved and transported to the nucleus, where it binds to antioxidant response elements (AREs) in the promoter region of proteasome subunit genes, thereby stimulating their transcription. In this review, we summarize the role of UPS impairment in aging and neurodegenerative disease etiology and consider the potential benefit of enhancing NFE2L1 function as a strategy to upregulate proteasome function and alleviate pathology in neurodegenerative diseases.

Keywords: NFE2L1; NRF2; aging; antioxidant response element; neurodegenerative diseases; proteasome

DOI: https://doi.org/10.3390/biology12091169

Cells. 2023 Sep 20. pii: 2318. [Epub ahead of print]12(18):

Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View.

Nitesh Sanghai, Geoffrey K Tranmer.

Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are defined by a myriad of complex aetiologies. Understanding the common biochemical molecular pathologies among NDDs gives an opportunity to decipher the overlapping and numerous cross-talk mechanisms of neurodegeneration. Numerous interrelated pathways lead to the progression of neurodegeneration. We present evidence from the past pieces of literature for the most usual global convergent hallmarks like ageing, oxidative stress, excitotoxicity-induced calcium butterfly effect, defective proteostasis including chaperones, autophagy, mitophagy, and proteosome networks, and neuroinflammation. Herein, we applied a holistic approach to identify and represent the shared mechanism across NDDs. Further, we believe that this approach could be helpful in identifying key modulators across NDDs, with a particular focus on AD, PD, and ALS. Moreover, these concepts could be applied to the development and diagnosis of novel strategies for diverse NDDs.

Keywords: Alzheimer’s disease; Parkinson’s disease; ageing; amyotrophic lateral sclerosis; autophagy; calcium butterfly effect; chaperones; excitotoxicity; mitophagy; neurodegenerative diseases; neuroinflammation; oxidative stress; proteostasis

DOI: https://doi.org/10.3390/cells12182318