PLK2 disrupts autophagic flux to promote SNCA/α-synuclein pathology DOI Creative Commons
Chuang Zhang, Zhan-Peng Huang, Xinyue Huang

et al.

Autophagy, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 21

Published: Jan. 8, 2025

The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology Parkinson disease (PD). PLK2 (polo like kinase 2) an evolutionarily conserved serine/threonine that more abundant in the brains all family members, highly expressed PD, linked to SNCA deposition. However, addition its role phosphorylating SNCA, PD mechanisms involved triggering neurodegeneration remain unclear. Here, we found regulated independently S129. Overexpression promoted preformed fibril (PFF)-induced wild-type mutant SNCAS129A. Genetic or pharmacological inhibition attenuated deposition neurotoxicity. Mechanistically, exacerbated propagation by impeding clearance aggregates blocking macroautophagic/autophagic flux. We further showed phosphorylated S1098 DCTN1 (dynactin 1), protein controls movement organelles, leading impaired autophagosome-lysosome fusion. Furthermore, genetic suppression alleviated motor dysfunction vivo. Our findings suggest negatively regulates autophagy, promoting pathology, suggesting for PD.

Language: Английский

Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration DOI Creative Commons
Wen Li, Jiayi Li

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: March 26, 2024

Proteinopathy, defined as the abnormal accumulation of proteins that eventually leads to cell death, is one most significant pathological features neurodegenerative diseases. Tauopathies, represented by Alzheimer's disease (AD), and synucleinopathies, Parkinson's (PD), show similarities in multiple aspects. AD manifests extrapyramidal symptoms while dementia also a major sign advanced PD. We other researchers have sequentially shown cross-seeding phenomenon α-synuclein (α-syn) tau, reinforcing pathologies between synucleinopathies tauopathies. The highly overlapping clinical imply shared pathogenic mechanisms two groups disease. diagnostic therapeutic strategies seemingly appropriate for distinct may apply broader spectrum. Therefore, clear understanding overlaps divergences tauopathy synucleinopathy critical unraveling nature complicated associations among In this review, we discuss diverse characteristics tauopathies from aspects genetic causes, manifestations, progression potential common approaches targeting pathology, aim provide timely update setting scheme classification novel insights into development

Language: Английский

Citations

11
Elevated α-synuclein levels inhibit mitophagic flux DOI Creative Commons

Inge Kinnart,

Liselot Manders,

Thibaut Heyninck

et al.

npj Parkinson s Disease, Journal Year: 2024, Volume and Issue: 10(1)

Published: April 9, 2024

Abstract The pathogenic effect of SNCA gene multiplications indicates that elevation wild-type α-synuclein levels is sufficient to cause Parkinson’s disease (PD). Mitochondria have been proposed be a major target α-synuclein-induced damage. PINK1/parkin/DJ-1-mediated mitophagy defense strategy allows cells selectively eliminate severely damaged mitochondria. Here, we quantified mitophagic flux and non-mitochondrial autophagic in three models increased expression: 1/ Drosophila melanogaster transgenically express human mutant flight muscle; 2/human skin fibroblasts transfected with or β-synuclein; 3/human induced pluripotent stem cell (iPSC)-derived neurons carrying an extra copy under control doxycycline-inducible promoter, allowing titratable upregulation. In each model, elevated potently suppressed flux, while autophagy was preserved. neurons, twofold increase already induce this effect. PINK1 parkin activation mitochondrial translocation DJ-1 after depolarization were not affected by Overexpression the actin-severing protein cofilin treatment CK666, inhibitor actin-related 2/3 (Arp2/3) complex, rescued α-synuclein, suggesting excessive actin network stabilization mediated defect. conclusion, inhibit flux. Disruption dynamics may play key role

Language: Английский

Citations

8
Role of Ubiquitin–Proteasome and Autophagy-Lysosome Pathways in α-Synuclein Aggregate Clearance DOI

Subhashree Sahoo,

Amrita Arpita Padhy,

Varsha Kumari

et al.

Molecular Neurobiology, Journal Year: 2022, Volume and Issue: 59(9), P. 5379 - 5407

Published: June 14, 2022

Language: Английский

Citations

37
Acidic nanoparticles protect against α‐synuclein‐induced neurodegeneration through the restoration of lysosomal function DOI
Marie-Laure Arotçarena, Federico N. Soria, Anthony Cunha

et al.

Aging Cell, Journal Year: 2022, Volume and Issue: 21(4)

Published: March 23, 2022

Abstract Parkinson's disease (PD) is an age‐related neurodegenerative disorder characterized by the loss of dopaminergic neurons in substantia nigra, associated with accumulation misfolded α‐synuclein and lysosomal impairment, two events deemed interconnected. Protein aggregation linked to defects degradation systems such as autophagy‐lysosomal pathway, while dysfunction partly related compromised acidification. We have recently proven that acidic nanoparticles (aNPs) can re‐acidify lysosomes ameliorate neurotoxin‐mediated neurodegeneration mice. However, no lysosome‐targeted approach has yet been tested synucleinopathy models vivo. Here, we show aNPs increase through enhancing activity vitro. further demonstrate vivo protect nigral from cell death, pathology, restore function mice injected PD patient‐derived Lewy body extracts carrying toxic aggregates. Our results support re‐acidification a disease‐modifying strategy for treatment other proteinopathies.

Language: Английский

Citations

34
Novel Insight into Functions of Transcription Factor EB (TFEB) in Alzheimer’s Disease and Parkinson’s Disease DOI Creative Commons
Jing Yang, Wei Zhang,

Shugeng Zhang

et al.

Aging and Disease, Journal Year: 2023, Volume and Issue: 14(3), P. 652 - 652

Published: Jan. 1, 2023

A key pathological feature of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD) and Parkinson’s (PD) is the accumulation aggregated misfolded protein aggregates with limited effective therapeutic agents. TFEB (transcription factor EB), a regulator lysosomal biogenesis autophagy, plays pivotal role in degradation has thus been regarded promising target for these NDs. Here, we systematically summarize molecular mechanisms function regulation. We then discuss roles autophagy-lysosome pathways major including AD PD. Finally, illustrate small molecule activators protective NDs animal models, which show great potential being further developed into novel anti-neurodegenerative Overall, targeting enhancing autophagy may represent opportunity discovery disease-modifying therapeutics disorders though more in-depth basic clinical studies are required future.

Language: Английский

Citations

17
Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites DOI Creative Commons
Stephanie Vrijsen, Céline Vrancx,

Mara Del Vecchio

et al.

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: June 21, 2022

Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset sporadic originate from a gradually disrupted organellar homeostasis. Herein, endolysosomal abnormalities, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and altered lipid metabolism commonly observed early preclinical stages of major NDs, including Parkinson's (PD) Alzheimer's (AD). Among the multitude underlying defective molecular mechanisms that have been suggested past decades, dysregulation inter-organellar communication through so-called membrane contact sites (MCSs) is becoming increasingly apparent. Although MCSs exist between almost every other type subcellular organelle, to date, most focus has put on ER mitochondria given these compartments critical neuronal survival. Contributions MCSs, notably those with endolysosomes droplets emerging, supported as well by genetic studies, identifying genes functionally involved lysosomal In review, we summarize identity organelle interactome yeast mammalian cells, critically evaluate evidence supporting contribution disturbed general homeostasis taking PD AD examples.

Language: Английский

Citations

26
Neuroinflammation and Autophagy in Parkinson’s Disease—Novel Perspectives DOI Open Access
D. Minchev, Maria Kazakova, Victoria Sarafian

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(23), P. 14997 - 14997

Published: Nov. 30, 2022

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. It characterized by accumulation of α-Synuclein aggregates and degeneration dopaminergic neurons in substantia nigra midbrain. Although exact mechanisms neuronal PD remain largely elusive, various pathogenic factors, such as cytotoxicity, mitochondrial dysfunction, oxidative stress, pro-inflammatory may significantly impair normal function promote apoptosis. In this context, neuroinflammation autophagy have emerged crucial processes that contribute to loss development. They are regulated a complex interconnected manner involving known PD-associated genes. This review summarizes evidence implication delineates role inflammatory factors autophagy-related proteins condition. also illustrates particular significance plasma serum immune markers their potential provide personalized approach diagnosis treatment.

Language: Английский

Citations

26
Organization of the autophagy pathway in neurons DOI Creative Commons
David K. Sidibe, Maria C. Vogel, Sandra Maday

et al.

Current Opinion in Neurobiology, Journal Year: 2022, Volume and Issue: 75, P. 102554 - 102554

Published: May 29, 2022

Language: Английский

Citations

24
Molecular Insights into Aggrephagy: Their Cellular Functions in the Context of Neurodegenerative Diseases DOI Creative Commons

Valentín Cóppola-Segovia,

Fulvio Reggiori

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(15), P. 168493 - 168493

Published: Feb. 14, 2024

Protein homeostasis or proteostasis is an equilibrium of biosynthetic production, folding and transport proteins, their timely efficient degradation. Proteostasis guaranteed by a network protein quality control systems aimed at maintaining the proteome functional avoiding accumulation potentially cytotoxic proteins. Terminal unfolded dysfunctional proteins can be directly turned over ubiquitin-proteasome system (UPS) first amassed into aggregates prior to Aggregates also disposed lysosomes selective type autophagy known as aggrephagy, which relies on set so-called receptors (SARs) adaptor Failure in eliminating aggregates, due defects have devastating effects underscored several neurodegenerative diseases proteinopathies, are characterized mostly formed specific disease-associated, aggregate-prone depending clinical pathology. Despite its medical relevance, however, process aggrephagy far from being understood. Here we review findings that helped assigning possible function SARs context highlight interplay between pathogenesis proteinopathies.

Language: Английский

Citations

5
α-Synuclein: Multiple pathogenic roles in trafficking and proteostasis pathways in Parkinson’s disease DOI

Annie J. Zalon,

Drew J. Quiriconi,

Caleb Pitcairn

et al.

The Neuroscientist, Journal Year: 2024, Volume and Issue: 30(5), P. 612 - 635

Published: Feb. 29, 2024

Parkinson's disease (PD) is a common age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in midbrain. A hallmark both familial and sporadic PD presence Lewy body inclusions composed mainly aggregated α-synuclein (α-syn), presynaptic protein encoded

Language: Английский

Citations

5