Fluid Biomarkers for Synaptic Dysfunction and Loss

Biomarker Insights, Journal Year: 2020, Volume and Issue: 15, P. 117727192095031 - 117727192095031

Published: Jan. 1, 2020

Synapses are the site for brain communication where information is transmitted between neurons and stored memory formation. Synaptic degeneration a global early pathogenic event in neurodegenerative disorders with reduced levels of pre- postsynaptic proteins being recognized as core feature Alzheimer’s disease (AD) pathophysiology. Together AD, other neurodevelopmental show altered synaptic homeostasis an important event, due to that, they commonly referred synaptopathies. The exact mechanisms synapse dysfunction different diseases not well understood their study would help understanding role degeneration, differences commonalities among them highlight candidate biomarkers specific disorders. assessment cerebrospinal fluid (CSF), which can reflect patients cognitive disorders, keen area interest. Substantial research efforts now directed toward investigation CSF pathology improve diagnosis at stage monitor clinical progression. In this review, we will first summarize pathological events that lead loss then discuss available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, α-syn) emerging vesicle glycoprotein 2A neuronal pentraxins) dysfunction, while highlighting possible utilities, specificity, technical challenges detection.

Language: Английский

---

Do Lewy bodies contain alpha-synuclein fibrils? and Does it matter? A brief history and critical analysis of recent reports

Neurobiology of Disease, Journal Year: 2020, Volume and Issue: 141, P. 104876 - 104876

Published: April 25, 2020

Several lines of evidence from neuropathological studies, human genetics, in vitro aggregation studies and cellular animal models support the hypothesis that aSyn plays a central role formation Lewy pathologies. These are cytoplasmic proteinaceous lipid-rich inclusions represent key pathological hallmarks Parkinson’s disease (PD) other neurodegenerative diseases, collectively referred to as synucleinopathies. For decades, light microscopy electron these have consistently shown they rich filamentous structures exhibit distinct distribution organizational patterns depending on where occur brain (e.g., classical brain-stem bodies (LBs) cortical LBs) type Although identity protein form filaments was subject debate for discovery PD-linked mutations, demonstration LBs enriched insoluble forms aSyn, ability fibrils similar dimensions led convergence components LBs. In recent study, Shahmoradian et al used combination advanced immunofluorescence based imaging techniques investigate structure, composition, architecture postmortem tissues individuals with PD or synucleinopathies (Shahmoradian al., 2019). The paper’s main conclusions suggest “lipid membrane fragments distorted organelles together non-fibrillar αSyn structural building blocks pathology”. Their proposal devoid LB occurs independently fibril casts doubts substantial body work foundation many current basic translational research programs academia industry. this article, I present critical analysis their data claims context existing literature addition, examine extent which findings proposed mechanisms consistent supported by experimental evidence. results caution against overinterpretation observations single report, especially given limitations approaches more collaborative systematic efforts revisit characterize pathologies at biochemical, morphological level.

Language: Английский

---

Insulin Resistance Promotes Parkinson’s Disease through Aberrant Expression of α-Synuclein, Mitochondrial Dysfunction, and Deregulation of the Polo-Like Kinase 2 Signaling

Cells, Journal Year: 2020, Volume and Issue: 9(3), P. 740 - 740

Published: March 17, 2020

Background: Insulin resistance (IR), considered a hallmark of diabetes at the cellular level, is implicated in pre-diabetes, results type 2 diabetes, and negatively affects mitochondrial function. Diabetes increasingly associated with enhanced risk developing Parkinson’s disease (PD); however, underlying mechanism remains unclear. This study investigated probable culpability IR pathogenesis PD. Methods: Using MitoPark mice vivo models, was induced by high-fat diet protracted pulse-stimulation 100 nM insulin treatment neuronal cells, vitro to determine molecular mechanism(s) altered functions PD, including dysfunction α-synuclein (SNCA) aberrant expression. Findings: We observed increased SNCA expression dopaminergic (DA) neurons both wild-type diabetic mice, coupled degeneration DA mice. Ex vivo, differentiated human neurons, reactive oxygen species (ROS) levels, as well depolarization. Moreover, we demonstrated concomitant hyperactivation polo-like kinase-2 (PLK2), upregulated p-SNCA (Ser129) proteinase K-resistant proteins level SH-SY5Y however inhibition PLK2 reversed IR-related increases phosphorylated total SNCA. Similarly, overexpression peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC)-1α suppressed ROS production, repressed hyperactivity, resulted downregulation Ser129-phosphorylated cells. Conclusions: These findings demonstrate that IR-associated promotes development progression PD through PLK2-mediated dysfunction, signaling, suggesting therapeutic targetability and/or potential novel disease-modifying strategies patients

Language: Английский

---

Synapsin Condensates Recruit alpha-Synuclein

Journal of Molecular Biology, Journal Year: 2021, Volume and Issue: 433(12), P. 166961 - 166961

Published: March 25, 2021

Neurotransmission relies on the tight spatial and temporal regulation of synaptic vesicle (SV) cycle. Nerve terminals contain hundreds SVs that form clusters. These clusters represent a distinct liquid phase in which one component are other synapsin 1, highly abundant protein. Another major family disordered proteins at presynapse includes synucleins, most notably α-synuclein. The precise physiological role α-synuclein physiology remains elusive, albeit its has been implicated nearly all steps SV To determine effect phase, we employ reconstitution approach using natively purified from rat brains heterologous cell system to generate condensates. We demonstrate condensates recruit α-synuclein, while enriched into these condensates, still maintains high mobility. presence enhances rate synapsin/α-synuclein condensation, suggesting act as catalyzers for formation Notably, salt protein concentrations, alone is not able cluster isolated SVs. Excess disrupts kinetics synapsin/SV condensate formation, indicating molar ratio between important assembling functional Understanding molecular mechanism interactions nerve crucial clarifying pathogenesis synucleinopathies, where lipid organelles accumulate insoluble intracellular inclusions.

Language: Английский

---

Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 6216 - 6216

Published: June 1, 2022

α-Synuclein is a protein with molecular weight of 14.5 kDa and consists 140 amino acids encoded by the SNCA gene. Missense mutations gene duplications in cause hereditary Parkinson’s disease. Highly phosphorylated abnormally aggregated α-synuclein major component Lewy bodies found neuronal cells patients sporadic disease, dementia bodies, glial cytoplasmic inclusion oligodendrocytes multiple system atrophy. Aggregated cytotoxic plays central role pathogenesis above-mentioned synucleinopathies. In healthy brain, most unphosphorylated; however, more than 90% disease at Ser129, which presumed to be pathological significance. Several kinases catalyze Ser129 phosphorylation, but phosphorylation enzymes their relationship cellular toxicity from are not fully understood α-synucleinopathy. Consequently, this review focuses on pathogenic impact its during neurodegeneration process

Language: Английский

---

PGC-1s in the Spotlight with Parkinson’s Disease

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(7), P. 3487 - 3487

Published: March 28, 2021

Parkinson's disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss dopaminergic neurons mainly localized in substantia nigra pars compacta. In recent years, detailed analyses both genetic and idiopathic forms have led to better understanding molecular cellular pathways involved PD, pointing centrality mitochondrial dysfunctions pathogenic process. Failure quality control now considered hallmark disease. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family acts as master regulator biogenesis. Therefore, keeping PGC-1 level proper range fundamental guarantee functional neurons. Here we review major findings that tightly bond PD PGC-1s, raising important points might lead future investigations.

Language: Английский

---

The relationship of alpha-synuclein to mitochondrial dynamics and quality control

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: Aug. 26, 2022

Maintenance of mitochondrial health is essential for neuronal survival and relies upon dynamic changes in the network effective quality control mechanisms including mitochondrial-derived vesicle pathway mitophagy. Mitochondrial dysfunction has been implicated driving pathology several neurodegenerative diseases, Parkinson's disease (PD) where dopaminergic neurons substantia nigra are selectively degenerated. In addition, many genes with PD-associated mutations have defined functions organelle control, indicating that dysregulation may represent a key element pathology. The most well-characterized aspect PD relates to alpha-synuclein; an aggregation-prone protein forms intracellular Lewy-body inclusions. Details how alpha-synuclein exerts its toxicity not completely known, however, dysfunctional mitochondria observed both patients models Accordingly, association between function established. This alpha-synuclein's role transport, dynamics, control. Despite these relationships, there limited research defining direct linking dynamics this review, we will discuss current literature addressing provide insight into proposed promoting functional relationships. We also consider some alternative speculate what relationship might mean physiologically relation PD.

Language: Английский

---

Inter and intracellular mitochondrial transfer: Future of mitochondrial transplant therapy in Parkinson’s disease

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 159, P. 114268 - 114268

Published: Jan. 20, 2023

Parkinson's disease (PD) is marked by the gradual degeneration of dopaminergic neurons and intracellular build-up Lewy bodies rich in α-synuclein protein. This impairs various aspects mitochondria including generation ROS, biogenesis, dynamics, mitophagy etc. Mitochondrial dynamics are regulated through inter movement which mitochondrial trafficking within between cells. plays a significant role maintaining neuronal terms energy growth. Kinesin, dynein, myosin, rho GTPase (Miro), TRAK facilitate retrograde anterograde mitochondria. Enzymes such as Kinases along with Calcium (Ca2+), Adenosine triphosphate (ATP) genes PINK1 Parkin also involved. Extracellular vesicles, gap junctions, tunneling nanotubes control intercellular movement. The knowledge understanding these proteins, enzymes, molecules, movements have led to development transplant therapeutic approach for disorders involving dysfunction stroke, ischemia PD. A better pathways crucial establishing extracellular therapy reverting pathology Currently, techniques coculture, mitopunch mitoception being utilized pre-clinical stages should be further explored translational value. review highlights how affected during field PD underlined particular due recent developments potential that it holds near future.

Language: Английский

---

Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 15, 2023

PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces dysfunction impairs mitophagy, driving accumulation substrate pS65-Ubiquitin (pUb) in primary neurons vivo. synthesized MTK458, a brain penetrant small molecule binds stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 mediates clearance PFF seeding models vitro vivo reduces pUb. developed ultrasensitive assay quantify pUb levels plasma observed increase PD subjects correlates with progression, paralleling our observations models. Our combined findings from preclinical patient biofluids suggest pharmacological activation is worthy further study as therapeutic strategy modification PD.Discovery Disease biomarker candidate, (pUb)Plasma correlate status progression patients.Identification potent, activator, MTK458MTK458 selectively activates by stimulating dimerization stabilization PINK1/TOM complexMTK458 drives normalizes

Language: Английский

---

A topographical atlas of α-synuclein dosage and cell type-specific expression in adult mouse brain and peripheral organs

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

Published: March 19, 2024

Parkinson's disease (PD) is the second most common neurodegenerative worldwide and presents pathologically with Lewy pathology dopaminergic neurodegeneration. contains aggregated α-synuclein (αSyn), a protein encoded by SNCA gene which also mutated or duplicated in subset of familial PD cases. Due to its predominant presynaptic localization, immunostaining for results diffuse reactivity pattern, providing little insight into types cells expressing αSyn. As result, αSyn expression-driven cellular vulnerability has been difficult ascertain. Using combination knock-in mice that target nucleus (Snca

Language: Английский

---