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Article: Extensive accumulation of misfolded protein aggregates during natural aging and senescence.

Cuanalo-Contreras, Karina / Schulz, Jonathan / Mukherjee, Abhisek / Park, Kyung-Won / Armijo, Enrique / Soto, Claudio

2023 Volume 14, Page(s) 1090109

Abstract: Accumulation of misfolded protein aggregates is a hallmark event in many age-related protein misfolding disorders, including some of the most prevalent and insidious neurodegenerative diseases. Misfolded protein aggregates produce progressive cell damage, ...

Abstract	Accumulation of misfolded protein aggregates is a hallmark event in many age-related protein misfolding disorders, including some of the most prevalent and insidious neurodegenerative diseases. Misfolded protein aggregates produce progressive cell damage, organ dysfunction, and clinical changes, which are common also in natural aging. Thus, we hypothesized that aging is associated to the widespread and progressive misfolding and aggregation of many proteins in various tissues. In this study, we analyzed whether proteins misfold, aggregate, and accumulate during normal aging in three different biological systems, namely senescent cells,
Language	English
Publishing date	2023-01-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2022.1090109
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Article ; Online: Development of a novel pharmacophore model to screen specific inhibitors for the serine-threonine protein phosphatase calcineurin.

Mukherjee, Abhisek / Cuanalo-Contreras, Karina / Sood, Abha / Soto, Claudio

Biochemistry and biophysics reports

2022 Volume 31, Page(s) 101311

Abstract: Calcineurin (CaN) is a calcium/calmodulin-dependent serine/threonine phosphatase with a crucial role in cellular homeostasis. It is also the target of the Food and Drug Administration (FDA) approved immunosuppressant drugs FK506 and cyclosporine A. ... ...

Abstract	Calcineurin (CaN) is a calcium/calmodulin-dependent serine/threonine phosphatase with a crucial role in cellular homeostasis. It is also the target of the Food and Drug Administration (FDA) approved immunosuppressant drugs FK506 and cyclosporine A. Recent work from our group and others indicated that an uncontrolled increase in CaN activity causes synaptic dysfunction and neuronal death in various models of neurodegenerative diseases associated with calcium dysregulation. Furthermore, pharmacological normalization of CaN activity can prevent disease progression in animal models. However, none of the FDA-approved CaN inhibitors bind CaN directly, leading to adverse side effects. The development of direct CaN inhibitors is required to reduce off-target effects, but its highly conserved active site and similar mechanism of action with other protein serine/threonine phosphatases impose a significant challenge. In this work, we developed a novel pharmacophore model to screen for CaN-specific inhibitors. Then, we performed a virtual screen for molecules having the pharmacophore model. We also show that the molecules identified in this screen can inhibit CaN with a low micromolar IC
Language	English
Publishing date	2022-08-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2831046-9
ISSN	2405-5808 ; 2405-5808
ISSN (online)	2405-5808
ISSN	2405-5808
DOI	10.1016/j.bbrep.2022.101311
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Article ; Online: Development of a novel pharmacophore model to screen specific inhibitors for the serine-threonine protein phosphatase calcineurin

Abhisek Mukherjee / Karina Cuanalo-Contreras / Abha Sood / Claudio Soto

Biochemistry and Biophysics Reports, Vol 31, Iss , Pp 101311- (2022)

2022

Abstract	Calcineurin (CaN) is a calcium/calmodulin-dependent serine/threonine phosphatase with a crucial role in cellular homeostasis. It is also the target of the Food and Drug Administration (FDA) approved immunosuppressant drugs FK506 and cyclosporine A. Recent work from our group and others indicated that an uncontrolled increase in CaN activity causes synaptic dysfunction and neuronal death in various models of neurodegenerative diseases associated with calcium dysregulation. Furthermore, pharmacological normalization of CaN activity can prevent disease progression in animal models. However, none of the FDA-approved CaN inhibitors bind CaN directly, leading to adverse side effects. The development of direct CaN inhibitors is required to reduce off-target effects, but its highly conserved active site and similar mechanism of action with other protein serine/threonine phosphatases impose a significant challenge. In this work, we developed a novel pharmacophore model to screen for CaN-specific inhibitors. Then, we performed a virtual screen for molecules having the pharmacophore model. We also show that the molecules identified in this screen can inhibit CaN with a low micromolar IC50. Interestingly, the inhibitors identified from the screen do not inhibit phosphoprotein phosphatase 2A, a member of the serine/threonine phosphatase family that shares 43% sequence identity with the CaN active site. The pharmacophore model that we developed and validated in this work may help to accelerate the development of specific CaN inhibitors.
Keywords	Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
Subject code	500
Language	English
Publishing date	2022-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Role of Andaman and Nicobar Islands in eddy formation along western boundary of the Bay of Bengal.

Mukherjee, A / Chatterjee, Abhisek / Francis, P A

Scientific reports

2019 Volume 9, Issue 1, Page(s) 10152

Abstract: Eddies along western boundary of the Bay of Bengal (WBoB) play an important role in regulating regional climate and marine productivity of the north Indian Ocean. In this paper, role of Andaman and Nicobar islands (ANIs) in the formation of eddies along ... ...

Abstract	Eddies along western boundary of the Bay of Bengal (WBoB) play an important role in regulating regional climate and marine productivity of the north Indian Ocean. In this paper, role of Andaman and Nicobar islands (ANIs) in the formation of eddies along the WBoB is studied using an ocean general circulation model. Our analysis shows that, in the absence of ANIs, there is a significant reduction in the total number of mesoscale eddies in this region. The impact is particularly evident for the cyclonic eddies as a reduction of ~50% can be noticed in the absence of the islands. In contrast, influence of ANIs on anticyclonic eddies is not homogeneous in the WBoB; while absence of ANIs significantly increases anticyclonic eddies in the central part of the WBoB, a decrease can be noticed in the southern part. We further show that the reduction in number of cyclonic eddies along the WBoB is primarily driven by reduced baroclinic and barotropic instabilities. This process is more conspicuous during winter (October-January) season compared to summer (June-September) and spring (February-May) seasons.
Language	English
Publishing date	2019-07-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-46542-9
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Article ; Online: Role of Andaman and Nicobar Islands in eddy formation along western boundary of the Bay of Bengal

A. Mukherjee / Abhisek Chatterjee / P. A. Francis

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 10

Abstract: Abstract Eddies along western boundary of the Bay of Bengal (WBoB) play an important role in regulating regional climate and marine productivity of the north Indian Ocean. In this paper, role of Andaman and Nicobar islands (ANIs) in the formation of ... ...

Abstract	Abstract Eddies along western boundary of the Bay of Bengal (WBoB) play an important role in regulating regional climate and marine productivity of the north Indian Ocean. In this paper, role of Andaman and Nicobar islands (ANIs) in the formation of eddies along the WBoB is studied using an ocean general circulation model. Our analysis shows that, in the absence of ANIs, there is a significant reduction in the total number of mesoscale eddies in this region. The impact is particularly evident for the cyclonic eddies as a reduction of ~50% can be noticed in the absence of the islands. In contrast, influence of ANIs on anticyclonic eddies is not homogeneous in the WBoB; while absence of ANIs significantly increases anticyclonic eddies in the central part of the WBoB, a decrease can be noticed in the southern part. We further show that the reduction in number of cyclonic eddies along the WBoB is primarily driven by reduced baroclinic and barotropic instabilities. This process is more conspicuous during winter (October–January) season compared to summer (June–September) and spring (February–May) seasons.
Keywords	Medicine ; R ; Science ; Q
Subject code	551
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
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Article ; Online: Prion-Like Protein Aggregates and Type 2 Diabetes.

Mukherjee, Abhisek / Soto, Claudio

Cold Spring Harbor perspectives in medicine

2017 Volume 7, Issue 5

Abstract: Type 2 diabetes (T2D) is a highly prevalent metabolic disease characterized by chronic insulin resistance and β-cell dysfunction and loss, leading to impaired insulin release and hyperglycemia. Although the mechanism responsible for β-cell dysfunction ... ...

Abstract	Type 2 diabetes (T2D) is a highly prevalent metabolic disease characterized by chronic insulin resistance and β-cell dysfunction and loss, leading to impaired insulin release and hyperglycemia. Although the mechanism responsible for β-cell dysfunction and death is not completely understood, recent findings suggest that the accumulation of misfolded aggregates of the islet amyloid polypeptide (IAPP) in the islets of Langerhans may play an important role in pancreatic damage. Misfolding and aggregation of diverse proteins and their accumulation as amyloid in different organs is the hallmark feature in a group of chronic, degenerative diseases termed protein misfolding disorders (PMDs). PMDs include highly prevalent human illnesses such as Alzheimer's and Parkinson's disease, as well as more than 25 rarer disorders. Among them, prion diseases are unique because the pathology can be transmitted by a proteinaceous infectious agent, termed a prion, which induces disease by propagating protein misfolding and aggregation. This phenomenon has a striking resemblance to the process of protein misfolding and aggregation in all of the PMDs, suggesting that misfolded aggregates have an intrinsic potential to be transmissible. Indeed, recent studies have shown that the pathological hallmarks of various PMDs can be induced in vivo under experimental conditions by inoculating tissue extracts containing protein aggregates into animal models. In this review, we describe our current understanding of the molecular mechanism underlying the prion-like transmission of protein aggregates and its possible role in T2D.
MeSH term(s)	Animals ; Brain/physiopathology ; Diabetes Mellitus, Type 2/etiology ; Diabetes Mellitus, Type 2/metabolism ; Humans ; Islet Amyloid Polypeptide/metabolism ; Pancreas/physiopathology ; Prions/metabolism ; Protein Aggregates ; Protein Folding ; Proteostasis Deficiencies/metabolism
Chemical Substances	Islet Amyloid Polypeptide ; Prions ; Protein Aggregates
Language	English
Publishing date	2017-05-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a024315
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Article ; Online: Lewy Body-like Pathology and Loss of Dopaminergic Neurons in Midbrain Organoids Derived from Familial Parkinson's Disease Patient.

Becerra-Calixto, Andrea / Mukherjee, Abhisek / Ramirez, Santiago / Sepulveda, Sofia / Sinha, Tirthankar / Al-Lahham, Rabab / De Gregorio, Nicole / Gherardelli, Camila / Soto, Claudio

Cells

2023 Volume 12, Issue 4

Abstract: Progressive accumulation of α-Synuclein (αSyn) in Lewy bodies (LBs) and loss of dopaminergic (DA) neurons are the hallmark pathological features of Parkinson's disease (PD). Although currently available in vitro and in vivo models have provided crucial ... ...

Abstract	Progressive accumulation of α-Synuclein (αSyn) in Lewy bodies (LBs) and loss of dopaminergic (DA) neurons are the hallmark pathological features of Parkinson's disease (PD). Although currently available in vitro and in vivo models have provided crucial information about PD pathogenesis, the mechanistic link between the progressive accumulation of αSyn into LBs and the loss of DA neurons is still unclear. To address this, it is critical to model LB formation and DA neuron loss, the two key neuropathological aspects of PD, in a relevant in vitro system. In this study, we developed a human midbrain-like organoid (hMBO) model of PD. We demonstrated that hMBOs generated from induced pluripotent stem cells (hiPSCs), derived from a familial PD (fPD) patient carrying αSyn gene (
MeSH term(s)	Humans ; Parkinson Disease/pathology ; Lewy Bodies ; Dopaminergic Neurons/pathology ; Mesencephalon/pathology ; Inclusion Bodies
Language	English
Publishing date	2023-02-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12040625
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Article ; Online: Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson's Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology.

Diao, Xiaojun / Wang, Fei / Becerra-Calixto, Andrea / Soto, Claudio / Mukherjee, Abhisek

Cells

2021 Volume 10, Issue 9

Abstract: Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson's disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates ... ...

Abstract	Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson's disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates in many different cellular and mouse models, these models generally lack LB features. Here, we generated midbrain dopaminergic (mDA) neuronal cultures from induced pluripotent stem cells (iPSCs) derived from familial PD (fPD) patients and healthy controls. We show that mDA neuronal cultures from fPD patients with A53T mutation and α-syn gene (
MeSH term(s)	Adult ; Case-Control Studies ; Cell Differentiation ; Dopamine/metabolism ; Dopaminergic Neurons/metabolism ; Dopaminergic Neurons/pathology ; Female ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Induced Pluripotent Stem Cells/pathology ; Male ; Middle Aged ; Mitochondria/metabolism ; Mitochondria/pathology ; Mutation ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Parkinson Disease/pathology ; Synucleinopathies/etiology ; Synucleinopathies/metabolism ; Synucleinopathies/pathology ; Young Adult ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism
Chemical Substances	SNCA protein, human ; alpha-Synuclein ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2021-09-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10092402
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Article ; Online: Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson’s Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology

Xiaojun Diao / Fei Wang / Andrea Becerra-Calixto / Claudio Soto / Abhisek Mukherjee

Cells, Vol 10, Iss 2402, p

2021 Volume 2402

Abstract: Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson’s disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates ... ...

Abstract	Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson’s disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates in many different cellular and mouse models, these models generally lack LB features. Here, we generated midbrain dopaminergic (mDA) neuronal cultures from induced pluripotent stem cells (iPSCs) derived from familial PD (fPD) patients and healthy controls. We show that mDA neuronal cultures from fPD patients with A53T mutation and α-syn gene ( SNCA ) triplication display pathological α-syn deposits, which spatially and morphologically resemble LBs. Importantly, we did not find any apparent accumulation of pathological α-syn in mDA neuronal culture derived from a healthy donor. Furthermore, we show that there are morphological abnormalities in the mitochondrial network in mDA neuronal cultures from fPD patients. Consequently, these cells were more susceptible to mitochondrial damage compared with healthy donor-derived mDA neuronal cultures. Our results indicate that the iPSC-derived mDA neuronal culture platform can be used to investigate the spatiotemporal appearance of LBs, as well as their composition, architecture, and relationship with mitochondrial abnormalities.
Keywords	Parkinson’s disease ; iPSC ; dopaminergic neurons ; α-synuclein aggregates ; Lewy bodies ; mitochondria ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Mitochondrial transplant to replenish damaged mitochondria: A novel therapeutic strategy for neurodegenerative diseases?

Mukherjee, Abhisek / Becerra Calixto, Andrea D / Chavez, Melissa / Delgado, Jean Paul / Soto, Claudio

Progress in molecular biology and translational science

2020 Volume 177, Page(s) 49–63

Abstract: Neurodegenerative diseases are currently some of the most debilitating and incurable illness, including highly prevalent disorders, such as Alzheimer's and Parkinson's disease. Despite impressive advances in understanding the molecular basis of ... ...

Abstract	Neurodegenerative diseases are currently some of the most debilitating and incurable illness, including highly prevalent disorders, such as Alzheimer's and Parkinson's disease. Despite impressive advances in understanding the molecular basis of neurodegenerative diseases, several clinical trials have failed in identifying drugs that successfully delay or stop disease progression. New targets are likely necessary to successfully combat these devastating diseases. In this chapter, we review the evidence indicating that impairment in the cellular energy machinery in the form of mitochondrial damage and dysfunction may be at the root of neurodegeneration. We also propose that transplant of functional isolated mitochondria may overcome the energetic damage and delay the progression of neurodegenerative diseases.
MeSH term(s)	Humans ; Mitochondria ; Mitochondrial Diseases/drug therapy ; Neurodegenerative Diseases/drug therapy ; Parkinson Disease/therapy
Language	English
Publishing date	2020-11-24
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2471995-X
ISSN	1878-0814 ; 0079-6603 ; 1877-1173
ISSN (online)	1878-0814
ISSN	0079-6603 ; 1877-1173
DOI	10.1016/bs.pmbts.2020.10.001
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