Hsp70 chaperone blocks α-synuclein oligomer formation via a novel engagement mechanism

Tao, Jiahui; Berthet, Amandine; Citron, Y. Rose; Tsiolaki, Paraskevi L.; Stanley, Robert F.; Gestwicki, Jason E.; Agard, David A.; McConlogue, Lisa

doi:10.1016/j.jbc.2021.100613

Cited by 32 publications

(27 citation statements)

References 74 publications

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“…Although sacsin has been confirmed to be the causative factor of ARSACS, its impact on other diseases should be investigated, especially given the limited reports on its functions, which focus on chaperon interactions with Hsp70 and mitochondrial homeostasis [ 3 , 21 ]. Since the pathomechanisms of ARSACS may share similar pathways with other neurodegenerative diseases, such as AD, PD, ALS and CJD, it will be crucial to investigate the consequences of the gain or loss of functions [ 125 , 126 , 127 , 128 , 129 ]. The study by Morani et al suggested that multi-omic (proteomic, genomic, transcriptomic) analysis in ARSACS models could be promising in the disease’s diagnosis, as well as in discovering the specific disease-causing pathways and risk-modifying factors, especially in the development of therapeutics [ 36 ].…”

Section: Discussion and Future Insightsmentioning

confidence: 99%

“…Hsp70 seemed to play an essential role in protecting against prion misfolding and aggregation [ 127 ]. In Hsp70 knockout mice, prion propagation and toxicity was accelerated [ 128 ]. Lastly, Hsp70 could block alpha synuclein oligomerization through a noncanonical site in the C-terminal domain to exert a protective function against PD and other synucleopathies [ 128 ].…”

Section: Potential Involvement Of Sacs In Other Neurodegenerative Diseasesmentioning

confidence: 99%

“…In Hsp70 knockout mice, prion propagation and toxicity was accelerated [ 128 ]. Lastly, Hsp70 could block alpha synuclein oligomerization through a noncanonical site in the C-terminal domain to exert a protective function against PD and other synucleopathies [ 128 ]. These studies suggest that sacsin may contribute either directly or indirectly to neuroprotection against non-ataxia-related diseases.…”

Section: Potential Involvement Of Sacs In Other Neurodegenerative Diseasesmentioning

confidence: 99%

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Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

Bagaria

Bagyinszky

2022

IJMS

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.

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Section: Discussion and Future Insightsmentioning

confidence: 99%

Section: Potential Involvement Of Sacs In Other Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Potential Involvement Of Sacs In Other Neurodegenerative Diseasesmentioning

confidence: 99%

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Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

Bagaria

Bagyinszky

2022

IJMS

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“…Thus, small heat shock proteins (Hsp27 and αB-crystallin) bind to alpha-synuclein and effectively suppress its aggregation and fibrillation [ 40 , 41 , 42 , 43 , 44 ]. More complex ATP-dependent chaperones of the Hsp70 class have an even more pronounced effect on the transformation of alpha-synuclein [ 45 , 46 , 47 , 48 ]. The Hsp70 chaperones can prevent the formation of fibrils and oligomers not only in the presence of ATP but also in its absence [ 46 , 47 ].…”

Section: Influence Of Chaperones On Pathological Transformation Of Am...mentioning

confidence: 99%

Regulation by Different Types of Chaperones of Amyloid Transformation of Proteins Involved in the Development of Neurodegenerative Diseases

Muronetz

Kudryavtseva

Leisi

et al. 2022

IJMS

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The review highlights various aspects of the influence of chaperones on amyloid proteins associated with the development of neurodegenerative diseases and includes studies conducted in our laboratory. Different sections of the article are devoted to the role of chaperones in the pathological transformation of alpha-synuclein and the prion protein. Information about the interaction of the chaperonins GroE and TRiC as well as polymer-based artificial chaperones with amyloidogenic proteins is summarized. Particular attention is paid to the effect of blocking chaperones by misfolded and amyloidogenic proteins. It was noted that the accumulation of functionally inactive chaperones blocked by misfolded proteins might cause the formation of amyloid aggregates and prevent the disassembly of fibrillar structures. Moreover, the blocking of chaperones by various forms of amyloid proteins might lead to pathological changes in the vital activity of cells due to the impaired folding of newly synthesized proteins and their subsequent processing. The final section of the article discusses both the little data on the role of gut microbiota in the propagation of synucleinopathies and prion diseases and the possible involvement of the bacterial chaperone GroE in these processes.

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“…Heat shock-mediated or geldanamycin-induced induction of Hsp70 can prevent α-synuclein-induced cell death in yeast, Drosophila and mouse models of PD [ 179 , 180 , 181 ]. Thus, it has been shown that Hsp70 prevents the formation of toxic α-synuclein oligomers that subsequently aggregate into insoluble fibril-forming Levi bodies, which is considered the main cause of Parkinson’s disease [ 182 , 183 ]. In addition, Hsp70 in combination with Hsp40 and Hsp110 participates in the dissolution of α-synuclein amyloid fibrils to form α-synuclein monomers in vitro [ 17 , 18 , 19 ].…”

Section: Hsp70 Prevents Neurodegeneration and Promotes Memory Recovery In Alzheimer’s Disease Modelsmentioning

confidence: 99%

Role of a Heat Shock Transcription Factor and the Major Heat Shock Protein Hsp70 in Memory Formation and Neuroprotection

Zatsepina

Evgen’ev

Гарбуз

2021

Cells

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Heat shock proteins (Hsps) represent the most evolutionarily ancient, conserved, and universal system for protecting cells and the whole body from various types of stress. Among Hsps, the group of proteins with a molecular weight of 70 kDa (Hsp70) plays a particularly important role. These proteins are molecular chaperones that restore the native conformation of partially denatured proteins after exposure to proteotoxic forms of stress and are critical for the folding and intracellular trafficking of de novo synthesized proteins under normal conditions. Hsp70s are expressed at high levels in the central nervous system (CNS) of various animals and protect neurons from various types of stress, including heat shock, hypoxia, and toxins. Numerous molecular and behavioral studies have indicated that Hsp70s expressed in the CNS are important for memory formation. These proteins contribute to the folding and transport of synaptic proteins, modulate signaling cascades associated with synaptic activation, and participate in mechanisms of neurotransmitter release. In addition, HSF1, a transcription factor that is activated under stress conditions and mediates Hsps transcription, is also involved in the transcription of genes encoding many synaptic proteins, whose levels are increased in neurons under stress and during memory formation. Thus, stress activates the molecular mechanisms of memory formation, thereby allowing animals to better remember and later avoid potentially dangerous stimuli. Finally, Hsp70 has significant protective potential in neurodegenerative diseases. Increasing the level of endogenous Hsp70 synthesis or injecting exogenous Hsp70 reduces neurodegeneration, stimulates neurogenesis, and restores memory in animal models of ischemia and Alzheimer’s disease. These findings allow us to consider recombinant Hsp70 and/or Hsp70 pharmacological inducers as potential drugs for use in the treatment of ischemic injury and neurodegenerative disorders.

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Hsp70 chaperone blocks α-synuclein oligomer formation via a novel engagement mechanism

Cited by 32 publications

References 74 publications

Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

Regulation by Different Types of Chaperones of Amyloid Transformation of Proteins Involved in the Development of Neurodegenerative Diseases

Role of a Heat Shock Transcription Factor and the Major Heat Shock Protein Hsp70 in Memory Formation and Neuroprotection

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