Chaperones and Proteostasis: Role in Parkinson’s Disease

Joshi, Neha; Raveendran, Atchaya; Nagotu, Shirisha

doi:10.3390/diseases8020024

Cited by 15 publications

(8 citation statements)

References 211 publications

(297 reference statements)

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“…Hence, upregulating HSP70, either directly by overexpression or indirectly via inhibition of HSP90, could be a favorable therapeutic approach to PD. Furthermore, HSP90 was found to interact with α-syn and promote fibril maturation in an ATP-dependent manner [ 200 ], supporting the beneficial effect caused by the inhibition of these proteins. In addition, overexpression of HSPA5, one of the HSP70 family members, reduces aggregation of α-syn by a refolding activity and by protein degradation through the UPS [ 201 ].…”

Section: Parkinson’s Diseasementioning

confidence: 99%

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

Argueti-Ostrovsky

Alfahel

Kahn

et al. 2021

Cells

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Multiple neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are being suggested to have common cellular and molecular pathological mechanisms, characterized mainly by protein misfolding and aggregation. These large inclusions, most likely, represent an end stage of a molecular cascade; however, the soluble misfolded proteins, which take part in earlier steps of this cascade, are the more toxic players. These pathological proteins, which characterize each specific disease, lead to the selective vulnerability of different neurons, likely resulting from a combination of different intracellular mechanisms, including mitochondrial dysfunction, ER stress, proteasome inhibition, excitotoxicity, oxidative damage, defects in nucleocytoplasmic transport, defective axonal transport and neuroinflammation. Damage within these neurons is enhanced by damage from the nonneuronal cells, via inflammatory processes that accelerate the progression of these diseases. In this review, while acknowledging the hallmark proteins which characterize the most common NDDs; we place specific focus on the common overlapping mechanisms leading to disease pathology despite these different molecular players and discuss how this convergence may occur, with the ultimate hope that therapies effective in one disease may successfully translate to another.

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Section: Parkinson’s Diseasementioning

confidence: 99%

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

Argueti-Ostrovsky

Alfahel

Kahn

et al. 2021

Cells

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“…Evidently, an understanding of the effect of heat on a protein belongs to the realm of protein folding, which is a highly complex process and still not fully retractable—even less predictable—despite remarkable theoretical and technological achievements [ 19 , 20 , 21 , 22 ]. Although folding and refolding can be achieved with purified proteins in vitro, the role of the intracellular environment and interacting proteins, such as chaperons [ 23 , 24 ], which are relevant for a real-life survival, cannot be ignored. Many proteins also interact with RNA, both large and small, and a large variety of small molecules can act as regulators and modifiers [ 25 , 26 ].…”

Section: Rationale Of Choice Of Heat-relevant Organisms and Macrommentioning

confidence: 99%

Evolution of Protein Structure and Stability in Global Warming

Barik

2020

IJMS

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This review focuses on the molecular signatures of protein structures in relation to evolution and survival in global warming. It is based on the premise that the power of evolutionary selection may lead to thermotolerant organisms that will repopulate the planet and continue life in general, but perhaps with different kinds of flora and fauna. Our focus is on molecular mechanisms, whereby known examples of thermoresistance and their physicochemical characteristics were noted. A comparison of interactions of diverse residues in proteins from thermophilic and mesophilic organisms, as well as reverse genetic studies, revealed a set of imprecise molecular signatures that pointed to major roles of hydrophobicity, solvent accessibility, disulfide bonds, hydrogen bonds, ionic and π-electron interactions, and an overall condensed packing of the higher-order structure, especially in the hydrophobic regions. Regardless of mutations, specialized protein chaperones may play a cardinal role. In evolutionary terms, thermoresistance to global warming will likely occur in stepwise mutational changes, conforming to the molecular signatures, such that each “intermediate” fits a temporary niche through punctuated equilibrium, while maintaining protein functionality. Finally, the population response of different species to global warming may vary substantially, and, as such, some may evolve while others will undergo catastrophic mass extinction.

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“…The dysregulation of any of these processes, either protein synthesis, folding or elimination contributes to neuronal degeneration and ageing [ 75 ]. There are different cellular mechanisms that deal with the imbalance of protein homeostasis in PD including stabilization and refolding of target proteins by the chaperone system [ 76 , 77 ], degradation of misfolded or aggregated proteins through the ubiquitin–proteasome system (UPS), and the autophagic-lysosomal pathway (ALP) [ 78 , 79 ]. If these strategies fail or are insufficient to restore protein balance, dangerous insoluble proteins accumulate into intracellular deposits named aggresomes.…”

Section: Lrrk2 Homeostasis and Quality-control Mechanismsmentioning

confidence: 99%

LRRK2 and Proteostasis in Parkinson’s Disease

Pérez-Carrión

Posadas

Solera

et al. 2022

IJMS

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Parkinson’s disease is a neurodegenerative condition initially characterized by the presence of tremor, muscle stiffness and impaired balance, with the deposition of insoluble protein aggregates in Lewy’s Bodies the histopathological hallmark of the disease. Although different gene variants are linked to Parkinson disease, mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are one of the most frequent causes of Parkinson’s disease related to genetic mutations. LRRK2 toxicity has been mainly explained by an increase in kinase activity, but alternative mechanisms have emerged as underlying causes for Parkinson’s disease, such as the imbalance in LRRK2 homeostasis and the involvement of LRRK2 in aggregation and spreading of α-synuclein toxicity. In this review, we recapitulate the main LRRK2 pathological mutations that contribute to Parkinson’s disease and the different cellular and therapeutic strategies devised to correct LRRK2 homeostasis. In this review, we describe the main cellular control mechanisms that regulate LRRK2 folding and aggregation, such as the chaperone network and the protein-clearing pathways such as the ubiquitin–proteasome system and the autophagic-lysosomal pathway. We will also address the more relevant strategies to modulate neurodegeneration in Parkinson’s disease through the regulation of LRRK2, using small molecules or LRRK2 silencing.

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Chaperones and Proteostasis: Role in Parkinson’s Disease

Cited by 15 publications

References 211 publications

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

Evolution of Protein Structure and Stability in Global Warming

LRRK2 and Proteostasis in Parkinson’s Disease

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