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Article ; Online: Can We Treat Neurodegenerative Proteinopathies by Enhancing Protein Degradation?

Engelender, Simone / Stefanis, Leonidas / Oddo, Salvatore / Bellucci, Arianna

Movement disorders : official journal of the Movement Disorder Society

2022 Volume 37, Issue 7, Page(s) 1346–1359

Abstract: Neurodegenerative proteinopathies are defined as a class of neurodegenerative disorders, with either genetic or sporadic age-related onset, characterized by the pathological accumulation of aggregated protein deposits. These mainly include Alzheimer's ... ...

Abstract	Neurodegenerative proteinopathies are defined as a class of neurodegenerative disorders, with either genetic or sporadic age-related onset, characterized by the pathological accumulation of aggregated protein deposits. These mainly include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) as well as frontotemporal lobar degeneration (FTLD). The deposition of abnormal protein aggregates in the brain of patients affected by these disorders is thought to play a causative role in neuronal loss and disease progression. On that account, the idea of improving the clearance of pathological protein aggregates has taken hold as a potential therapeutic strategy. Among the possible approaches to pursue for reducing disease protein accumulation, there is the stimulation of the main protein degradation machineries of eukaryotic cells: the ubiquitin proteasomal system (UPS) and autophagy lysosomal pathway (ALP). Of note, several clinical trials testing the efficacy of either UPS- or ALP-active compounds are currently ongoing. Here, we discuss the main gaps and controversies emerging from experimental studies and clinical trials assessing the therapeutic efficacy of modulators of either the UPS or ALP in neurodegenerative proteinopathies, to gather whether they may constitute a real gateway from these disorders. © 2022 International Parkinson and Movement Disorder Society.
MeSH term(s)	Amyotrophic Lateral Sclerosis ; Frontotemporal Lobar Degeneration ; Humans ; Protein Aggregates ; Proteins/metabolism ; Proteolysis ; Ubiquitin/metabolism
Chemical Substances	Protein Aggregates ; Proteins ; Ubiquitin
Language	English
Publishing date	2022-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	607633-6
ISSN	1531-8257 ; 0885-3185
ISSN (online)	1531-8257
ISSN	0885-3185
DOI	10.1002/mds.29058
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Article: SUMOylation in α-Synuclein Homeostasis and Pathology.

Savyon, Mor / Engelender, Simone

Frontiers in aging neuroscience

2020 Volume 12, Page(s) 167

Abstract: The accumulation and aggregation of α-synuclein are central to Parkinson's disease (PD), yet the molecular mechanisms responsible for these events are not fully understood. Post-translational modifications of α-synuclein regulate several of its ... ...

Abstract	The accumulation and aggregation of α-synuclein are central to Parkinson's disease (PD), yet the molecular mechanisms responsible for these events are not fully understood. Post-translational modifications of α-synuclein regulate several of its properties, including degradation, interaction with proteins and membranes, aggregation and toxicity. SUMOylation is a post-translational modification involved in various nuclear and extranuclear processes, such as subcellular protein targeting, mitochondrial fission and synaptic plasticity. Protein SUMOylation increases in response to several stressful situations, from viral infections to trauma. In this framework, an increasing amount of evidence has implicated SUMOylation in several neurodegenerative diseases, including PD. This review will discuss recent findings in the role of SUMOylation as a regulator of α-synuclein accumulation, aggregation and toxicity, and its possible implication in neurodegeneration that underlies PD.
Keywords	covid19
Language	English
Publishing date	2020-06-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2020.00167
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Article ; Online: α-Synuclein fate: proteasome or autophagy?

Engelender, Simone

Autophagy

2012 Volume 8, Issue 3, Page(s) 418–420

Abstract: The accumulation of α-synuclein is critical for the development of Parkinson disease (PD), and unraveling the mechanisms that regulate α-synuclein levels is key to understanding the pathophysiology of the disease. We recently found that USP9X ... ...

Abstract	The accumulation of α-synuclein is critical for the development of Parkinson disease (PD), and unraveling the mechanisms that regulate α-synuclein levels is key to understanding the pathophysiology of the disease. We recently found that USP9X deubiquitinates α-synuclein, and that this process determines the partition of α-synuclein between the proteasomal and autophagy pathways. By manipulating USP9X levels, we observed that monoubiquitinated α-synuclein is degraded by the proteasome, whereas deubiquitination of α-synuclein favors its degradation by autophagy. As USP9X levels and activity are decreased in α-synucleinopathy brains, USP9X may now represent a novel target for PD.
MeSH term(s)	Autophagy ; Humans ; Models, Biological ; Parkinson Disease/metabolism ; Parkinson Disease/pathology ; Proteasome Endopeptidase Complex/metabolism ; Signal Transduction ; Ubiquitin Thiolesterase/metabolism ; Ubiquitination ; alpha-Synuclein/metabolism
Chemical Substances	USP9X protein, human ; alpha-Synuclein ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2012-02-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.19085
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Article ; Online: The Threshold Theory for Parkinson's Disease.

Engelender, Simone / Isacson, Ole

Trends in neurosciences

2017 Volume 40, Issue 1, Page(s) 4–14

Abstract: Parkinson's disease (PD) is recognized by the accumulation of α-synuclein within neurons. In contrast to the current ascending theory where α-synuclein would propagate from neuron to neuron, we now propose the threshold theory for PD based on evidence of ...

Abstract	Parkinson's disease (PD) is recognized by the accumulation of α-synuclein within neurons. In contrast to the current ascending theory where α-synuclein would propagate from neuron to neuron, we now propose the threshold theory for PD based on evidence of parallel degeneration of both central nervous system (CNS) and peripheral nervous system (PNS) in PD. The functional threshold is lower for the emergence of early symptoms before the classical motor symptoms of PD. This is due to the larger functional reserve of the midbrain dopamine and integrated basal ganglia motor systems to control movement. This threshold theory better accounts for the current neurobiology of PD symptom progression compared to the hypothesis that the disease ascends from the PNS to the CNS as proposed by Braak's hypothesis.
MeSH term(s)	Animals ; Brain/physiopathology ; Dopaminergic Neurons/physiology ; Humans ; Models, Neurological ; Parkinson Disease/physiopathology
Language	English
Publishing date	2017-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	282488-7
ISSN	1878-108X ; 0378-5912 ; 0166-2236
ISSN (online)	1878-108X
ISSN	0378-5912 ; 0166-2236
DOI	10.1016/j.tins.2016.10.008
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Zs.A 1442: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.

Dong, Jun / Chen, Li / Ye, Fei / Tang, Junhui / Liu, Bing / Lin, Jiacheng / Zhou, Pang-Hu / Lu, Bin / Wu, Min / Lu, Jia-Hong / He, Jing-Jing / Engelender, Simone / Meng, Qingtao / Song, Zhiyin / He, He

Nature communications

2024 Volume 15, Issue 1, Page(s) 168

Abstract: Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. ... ...

Abstract	Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.
MeSH term(s)	Mice ; Animals ; Lipid Metabolism/genetics ; Non-alcoholic Fatty Liver Disease/metabolism ; Endoplasmic Reticulum Stress ; Liver/metabolism ; Mitochondria/metabolism ; Liver Cirrhosis/pathology ; Endoplasmic Reticulum/metabolism
Language	English
Publishing date	2024-01-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-44057-6
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Article ; Online: Lipid and immune abnormalities causing age-dependent neurodegeneration and Parkinson's disease.

Hallett, Penelope J / Engelender, Simone / Isacson, Ole

Journal of neuroinflammation

2019 Volume 16, Issue 1, Page(s) 153

Abstract: This article describes pathogenic concepts and factors, in particular glycolipid abnormalities, that create cell dysfunction and synaptic loss in neurodegenerative diseases. By phenocopying lysosomal storage disorders, such as Gaucher disease and related ...

Abstract	This article describes pathogenic concepts and factors, in particular glycolipid abnormalities, that create cell dysfunction and synaptic loss in neurodegenerative diseases. By phenocopying lysosomal storage disorders, such as Gaucher disease and related disorders, age- and dose-dependent changes in glycolipid cell metabolism can lead to Parkinson's disease and related dementias. Recent results show that perturbation of sphingolipid metabolism can precede or is a part of abnormal protein handling in both genetic and idiopathic Parkinson's disease and Lewy body dementia. In aging and genetic predisposition with lipid disturbance, α-synuclein's normal vesicular and synaptic role may be detrimentally shifted toward accommodating and binding such lipids. Specific neuronal glycolipid, protein, and vesicular interactions create potential pathophysiology that is amplified by astroglial and microglial immune mechanisms resulting in neurodegeneration. This perspective provides a new logic for therapeutic interventions that do not focus on protein aggregation, but rather provides a guide to the complex biology and the common sequence of events that lead to age-dependent neurodegenerative disorders.
MeSH term(s)	Animals ; Brain/immunology ; Brain/metabolism ; Brain/pathology ; Humans ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/pathology ; Nerve Degeneration/immunology ; Nerve Degeneration/metabolism ; Nerve Degeneration/pathology ; Neurons/immunology ; Neurons/metabolism ; Neurons/pathology ; Parkinson Disease/immunology ; Parkinson Disease/metabolism ; Parkinson Disease/pathology ; alpha-Synuclein/metabolism ; tau Proteins/metabolism
Chemical Substances	alpha-Synuclein ; tau Proteins
Language	English
Publishing date	2019-07-22
Publishing country	England
Document type	Journal Article ; Review
ISSN	1742-2094
ISSN (online)	1742-2094
DOI	10.1186/s12974-019-1532-2
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Article ; Online: Ubiquitination of alpha-synuclein and autophagy in Parkinson's disease.

Engelender, Simone

Autophagy

2008 Volume 4, Issue 3, Page(s) 372–374

Abstract: alpha-Synuclein is mutated in Parkinson's disease (PD) and is found in cytosolic inclusions, called Lewy bodies, in sporadic forms of the disease. A fraction of alpha-synuclein purified from Lewy bodies is monoubiquitinated, but the role of this ... ...

Abstract	alpha-Synuclein is mutated in Parkinson's disease (PD) and is found in cytosolic inclusions, called Lewy bodies, in sporadic forms of the disease. A fraction of alpha-synuclein purified from Lewy bodies is monoubiquitinated, but the role of this monoubiquitination has been obscure. We now review recent data indicating a role of alpha-synuclein monoubiquitination in Lewy body formation and implicating the autophagic pathway in regulating these processes. The E3 ubiquitin-ligase SIAH is present in Lewy bodies and monoubiquitinates alpha-synuclein at the same lysines that are monoubiquitinated in Lewy bodies. Monoubiquitination by SIAH promotes the aggregation of alpha-synuclein into amorphous aggregates and increases the formation of inclusions within dopaminergic cells. Such effect is observed even at low monoubiquitination levels, suggesting that monoubiquitinated alpha-synuclein may work as a seed for aggregation. Accumulation of monoubiquitinated alpha-synuclein and formation of cytosolic inclusions is promoted by autophagy inhibition and to a lesser extent by proteasomal and lysosomal inhibition. Monoubiquitinated alpha-synuclein inclusions are toxic to cells and recruit PD-related proteins, such as synphilin-1 and UCH-L1. Altogether, the new data indicate that monoubiquitination might play an important role in Lewy body formation. Decreasing alpha- synuclein monoubiquitination, by preventing SIAH function or by stimulating autophagy, constitutes a new therapeutic strategy for Parkinson's disease.
MeSH term(s)	Autophagy/physiology ; Carrier Proteins/metabolism ; Humans ; Lewy Bodies/metabolism ; Nerve Tissue Proteins/metabolism ; Parkinson Disease/metabolism ; Parkinson Disease/pathology ; Ubiquitin Thiolesterase/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; alpha-Synuclein/metabolism
Chemical Substances	Carrier Proteins ; Nerve Tissue Proteins ; SNCAIP protein, human ; UCHL1 protein, human ; alpha-Synuclein ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Ubiquitin Thiolesterase (EC 3.4.19.12)
Language	English
Publishing date	2008-01-18
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.5604
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Article ; Online: Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.

Hao, Tianshu / Yu, Jianglong / Wu, Zhida / Jiang, Jie / Gong, Longlong / Wang, Bingjun / Guo, Hanze / Zhao, Huabin / Lu, Bin / Engelender, Simone / He, He / Song, Zhiyin

Nature communications

2023 Volume 14, Issue 1, Page(s) 4105

Abstract: Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. ... ...

Abstract	Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism. However, the mode and biological functions of mitochondria-lysosome communication remain largely unknown. Here, we show that hypoxia remodels normal tubular mitochondria into megamitochondria by inducing broad inter-mitochondria contacts and subsequent fusion. Importantly, under hypoxia, mitochondria-lysosome contacts are promoted, and certain lysosomes are engulfed by megamitochondria, in a process we term megamitochondria engulfing lysosome (MMEL). Both megamitochondria and mature lysosomes are required for MMEL. Moreover, the STX17-SNAP29-VAMP7 complex contributes to mitochondria-lysosome contacts and MMEL under hypoxia. Intriguingly, MMEL mediates a mode of mitochondrial degradation, which we termed mitochondrial self-digestion (MSD). Moreover, MSD increases mitochondrial ROS production. Our results reveal a mode of crosstalk between mitochondria and lysosomes and uncover an additional pathway for mitochondrial degradation.
MeSH term(s)	Humans ; Lysosomes ; Mitochondria ; Hypoxia ; Oxygen ; Digestion
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2023-07-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-39811-9
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Article ; Online: SIAH proteins regulate the degradation and intra-mitochondrial aggregation of PINK1: Implications for mitochondrial pathology in Parkinson's disease.

Abd Elghani, Fatimah / Safory, Hazem / Hamza, Haya / Savyon, Mor / Farhoud, Malik / Toren-Hershoviz, Michal / Vitic, Zagorka / Ebanks, Kirsten / Shani, Vered / Bisharat, Sleman / Shaulov, Lihi / Brodski, Claude / Song, Zhiyin / Bandopadhyay, Rina / Engelender, Simone

Aging cell

2022 Volume 21, Issue 12, Page(s) e13731

Abstract: Parkinson's disease (PD) is characterized by degeneration of neurons, particularly dopaminergic neurons in the substantia nigra. PD brains show accumulation of α-synuclein in Lewy bodies and accumulation of dysfunctional mitochondria. However, the ... ...

Abstract	Parkinson's disease (PD) is characterized by degeneration of neurons, particularly dopaminergic neurons in the substantia nigra. PD brains show accumulation of α-synuclein in Lewy bodies and accumulation of dysfunctional mitochondria. However, the mechanisms leading to mitochondrial pathology in sporadic PD are poorly understood. PINK1 is a key for mitophagy activation and recycling of unfit mitochondria. The activation of mitophagy depends on the accumulation of uncleaved PINK1 at the outer mitochondrial membrane and activation of a cascade of protein ubiquitination at the surface of the organelle. We have now found that SIAH3, a member of the SIAH proteins but lacking ubiquitin-ligase activity, is increased in PD brains and cerebrospinal fluid and in neurons treated with α-synuclein preformed fibrils (α-SynPFF). We also observed that SIAH3 is aggregated together with PINK1 in the mitochondria of PD brains. SIAH3 directly interacts with PINK1, leading to their intra-mitochondrial aggregation in cells and neurons and triggering a cascade of toxicity with PINK1 inactivation along with mitochondrial depolarization and neuronal death. We also found that SIAH1 interacts with PINK1 and promotes ubiquitination and proteasomal degradation of PINK1. Similar to the dimerization of SIAH1/SIAH2, SIAH3 interacts with SIAH1, promoting its translocation to mitochondria and preventing its ubiquitin-ligase activity toward PINK1. Our results support the notion that the increase in SIAH3 and intra-mitochondrial aggregation of SIAH3-PINK1 may mediate α-synuclein pathology by promoting proteotoxicity and preventing the elimination of dysfunctional mitochondria. We consider it possible that PINK1 activity is decreased in sporadic PD, which impedes proper mitochondrial renewal in the disease.
MeSH term(s)	Humans ; alpha-Synuclein/metabolism ; Parkinson Disease/metabolism ; Protein Kinases/metabolism ; Mitophagy ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitin
Chemical Substances	alpha-Synuclein ; Protein Kinases (EC 2.7.-) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Ubiquitin
Language	English
Publishing date	2022-10-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2113083-8
ISSN	1474-9726 ; 1474-9718
ISSN (online)	1474-9726
ISSN	1474-9718
DOI	10.1111/acel.13731
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Article ; Online: ATAD3B is a mitophagy receptor mediating clearance of oxidative stress-induced damaged mitochondrial DNA.

Shu, Li / Hu, Chao / Xu, Meng / Yu, Jianglong / He, He / Lin, Jie / Sha, Hongying / Lu, Bin / Engelender, Simone / Guan, Minxin / Song, Zhiyin

The EMBO journal

2021 Volume 40, Issue 8, Page(s) e106283

Abstract: Mitochondrial DNA (mtDNA) encodes several key components of respiratory chain complexes that produce cellular energy through oxidative phosphorylation. mtDNA is vulnerable to damage under various physiological stresses, especially oxidative stress. mtDNA ...

Abstract	Mitochondrial DNA (mtDNA) encodes several key components of respiratory chain complexes that produce cellular energy through oxidative phosphorylation. mtDNA is vulnerable to damage under various physiological stresses, especially oxidative stress. mtDNA damage leads to mitochondrial dysfunction, and dysfunctional mitochondria can be removed by mitophagy, an essential process in cellular homeostasis. However, how damaged mtDNA is selectively cleared from the cell, and how damaged mtDNA triggers mitophagy, remain mostly unknown. Here, we identified a novel mitophagy receptor, ATAD3B, which is specifically expressed in primates. ATAD3B contains a LIR motif that binds to LC3 and promotes oxidative stress-induced mitophagy in a PINK1-independent manner, thus promoting the clearance of damaged mtDNA induced by oxidative stress. Under normal conditions, ATAD3B hetero-oligomerizes with ATAD3A, thus promoting the targeting of the C-terminal region of ATAD3B to the mitochondrial intermembrane space. Oxidative stress-induced mtDNA damage or mtDNA depletion reduces ATAD3B-ATAD3A hetero-oligomerization and leads to exposure of the ATAD3B C-terminus at the mitochondrial outer membrane and subsequent recruitment of LC3 for initiating mitophagy. Furthermore, ATAD3B is little expressed in m.3243A > G mutated cells and MELAS patient fibroblasts showing endogenous oxidative stress, and ATAD3B re-expression promotes the clearance of m.3243A > G mutated mtDNA. Our findings uncover a new pathway to selectively remove damaged mtDNA and reveal that increasing ATAD3B activity is a potential therapeutic approach for mitochondrial diseases.
MeSH term(s)	ATPases Associated with Diverse Cellular Activities/chemistry ; ATPases Associated with Diverse Cellular Activities/genetics ; ATPases Associated with Diverse Cellular Activities/metabolism ; Animals ; Cells, Cultured ; DNA Damage ; DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Membrane Proteins/chemistry ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Microtubule-Associated Proteins/metabolism ; Mitochondrial Proteins/chemistry ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Mitophagy ; Oxidative Stress ; Protein Binding
Chemical Substances	ATAD3B protein, human ; DNA, Mitochondrial ; MAP1LC3A protein, human ; Membrane Proteins ; Microtubule-Associated Proteins ; Mitochondrial Proteins ; ATPases Associated with Diverse Cellular Activities (EC 3.6.4.-)
Language	English
Publishing date	2021-03-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2020106283
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