Carotid Body Resection Prevents Short-Term Spatial Memory Decline in Prediabetic Rats Without Changing Insulin Signaling in the Hippocampus and Prefrontal Cortex.

Individuals who develop type 2 diabetes (T2D) at an early age are at higher risk of developing neurodegenerative disorders such as Alzheimer's and Parkinson's disease. A shared dysfunctional characteristic between T2D and these neurodegenerative disorders is insulin resistance. Recently, it was shown that prediabetes animals and patients exhibited increased carotid body (CB) activity. Moreover, these organs are deeply involved in the development of metabolic diseases, since upon abolishment of their activity via carotid sinus nerve (CSN) resection, several dysmetabolic features of T2D were reverted. Herein, we investigated if CSN resection may also prevent cognitive impairment associated with brain insulin resistance. We explored a diet-induced prediabetes animal model where Wistar rats are kept in a high fat-high sucrose (HFHSu) diet for 20 weeks. We evaluated CSN resection effects on behavioral parameters and on insulin signaling-related proteins levels, in the prefrontal cortex and the hippocampus. HFHSu animals exhibited impaired short-term memory evaluated by the y-maze test. Remarkably, CSN resection prevented the development of this phenotype. HFHSu diet or CSN resection did not promote significant alterations in insulin signaling-associated proteins levels. Our findings suggest that CBs modulation might have a role in preventing short-term spatial memory deficits associated with peripheral dysmetabolic states.

Insulin-degrading enzyme: an ally against metabolic and neurodegenerative diseases.

Insulin-degrading enzyme (IDE) function goes far beyond its known proteolytic role as a regulator of insulin levels. IDE has a wide substrate promiscuity, degrading several proteins such as amyloid-ß peptide, glucagon, islet amyloid polypeptide (IAPP), and insulin-like growth factors, which have diverse physiological and pathophysiological functions. Importantly, IDE plays other non-proteolytic functions such as: a chaperone/dead-end chaperone, an E1-ubiquitin activating enzyme, and a proteasome modulator. It also responds as a heat shock protein, regulating cellular proteostasis. Notably, amyloidogenic proteins such as IAPP, amyloid-ß, and α-synuclein have been reported as substrates for IDE chaperone activity. This is of utmost importance as failure of IDE may result in increased protein aggregation, a key hallmark in the pathogenesis of beta cells in type 2 diabetes mellitus and of neurons in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In this review, we focus on the biochemical and biophysical properties of IDE and the regulation of its physiological functions. We further raise the hypothesis that IDE plays a central role in the pathological context of dysmetabolic and neurodegenerative diseases and discuss its potential as a therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hsp27 reduces glycation-induced toxicity and aggregation of alpha-synuclein.

α-synuclein (aSyn) is a major player in Parkinson's disease and a group of other disorders collectively known as synucleinopathies, but the precise molecular mechanisms involved are still unclear. aSyn, as virtually all proteins, undergoes a series of posttranslational modifications during its lifetime, which can affect its biology and pathobiology. We recently showed that glycation of aSyn by methylglyoxal (MGO) potentiates its oligomerization and toxicity, induces dopaminergic neuronal cell loss in mice, and affects motor performance in flies. Small heat-shock proteins (sHsps) are molecular chaperones that facilitate the folding of proteins or target misfolded proteins for clearance. Importantly, sHsps were shown to prevent aSyn aggregation and cytotoxicity. Upon treating cells with increasing amounts of methylglyoxal, we found that the levels of Hsp27 decreased in a dose-dependent manner. Therefore, we hypothesized that restoring the levels of Hsp27 in glycating environments could alleviate the pathogenicity of aSyn. Consistently, we found that Hsp27 reduced MGO-induced aSyn aggregation in cells, leading to the formation of nontoxic aSyn species. Remarkably, increasing the levels of Hsp27 suppressed the deleterious effects induced by MGO. Our findings suggest that in glycating environments, the levels of Hsp27 are important for modulating the glycation-associated cellular pathologies in synucleinopathies.

The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.

Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear. Here, we provide mechanistic insight into the interplay between sirtuin 2 and α-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies. We found that α-synuclein is acetylated on lysines 6 and 10 and that these residues are deacetylated by sirtuin 2. Genetic manipulation of sirtuin 2 levels in vitro and in vivo modulates the levels of α-synuclein acetylation, its aggregation, and autophagy. Strikingly, mutants blocking acetylation exacerbate α-synuclein toxicity in vivo, in the substantia nigra of rats. Our study identifies α-synuclein acetylation as a key regulatory mechanism governing α-synuclein aggregation and toxicity, demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies.

Correction: The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.

[This corrects the article DOI: 10.1371/journal.pbio.2000374.].

Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies.

α-Synuclein misfolding and aggregation is a hallmark in Parkinson's disease and in several other neurodegenerative diseases known as synucleinopathies. The toxic properties of α-synuclein are conserved from yeast to man, but the precise underpinnings of the cellular pathologies associated are still elusive, complicating the development of effective therapeutic strategies. Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced α-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. Glycation affected primarily the N-terminal region of α-synuclein, reducing membrane binding, impaired the clearance of α-synuclein, and promoted the accumulation of toxic oligomers that impaired neuronal synaptic transmission. Strikingly, using glycation inhibitors, we demonstrated that normal clearance of α-synuclein was re-established, aggregation was reduced, and motor phenotypes in Drosophila were alleviated. Altogether, our study demonstrates glycation constitutes a novel drug target that can be explored in synucleinopathies as well as in other neurodegenerative conditions.

Adenosine A2A Receptors Modulate α-Synuclein Aggregation and Toxicity.

Abnormal accumulation of aggregated α-synuclein (aSyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and related synucleinopathies. Recent studies suggest a neuroprotective role of adenosine A2A receptor (A2AR) antagonists in PD. Nevertheless, the precise molecular mechanisms underlying this neuroprotection remain unclear. We assessed the impact of A2AR blockade or genetic deletion (A2AR KO) on synaptic plasticity and neuronal cell death induced by aSyn oligomers. We found that impairment of LTP associated with aSyn exposure was rescued in A2AR KO mice or upon A2AR blockade, through an NMDA receptor-dependent mechanism. The mechanisms underlying these effects were evaluated in SH-SY5Y cells overexpressing aSyn and rat primary neuronal cultures exposed to aSyn. Cell death in both conditions was prevented by selective A2AR antagonists. Interestingly, blockade of these receptors did not interfere with aSyn oligomerization but, instead, reduced the percentage of cells displaying aSyn inclusions. Altogether, our data raise the possibility that the well-documented effects of A2AR antagonists involve the control of the latter stages of aSyn aggregation, thereby preventing the associated neurotoxicity. These findings suggest that A2AR represent an important target for the development of effective drugs for the treatment of PD and related synucleinopathies.

(Poly)phenols protect from α-synuclein toxicity by reducing oxidative stress and promoting autophagy.

Parkinson's disease (PD) is the most common movement neurodegenerative disorder and is associated with the aggregation of α-synuclein (αSyn) and oxidative stress, hallmarks of the disease. Although the precise molecular events underlying αSyn aggregation are still unclear, oxidative stress is known to contribute to this process. Therefore, agents that either prevent oxidative stress or inhibit αSyn toxicity are expected to constitute potential drug leads for PD. Both pre-clinical and clinical studies provided evidence that (poly)phenols, pure or in extracts, might protect against neurodegenerative disorders associated with oxidative stress in the brain. In this study, we analyzed, for the first time, a (poly)phenol-enriched fraction (PEF) from leaves of Corema album, and used in vitro and cellular models to evaluate its effects on αSyn toxicity and aggregation. Interestingly, the PEF promoted the formation of non-toxic αSyn species in vitro, and inhibited its toxicity and aggregation in cells, by promoting the autophagic flux and reducing oxidative stress. Thus, C. album (poly)phenols appear as promising cytoprotective compounds, modulating central events in the pathogenesis of PD, such as αSyn aggregation and the impairment of autophagy. Ultimately, the understanding of the molecular effects of (poly)phenols will open novel opportunities for the exploitation of their beneficial effects and for drug development.

Glycation in Parkinson's disease and Alzheimer's disease.

Glycation is a spontaneous age-dependent posttranslational modification that can impact the structure and function of several proteins. Interestingly, glycation can be detected at the periphery of Lewy bodies in the brain in Parkinson's disease. Moreover, α-synuclein can be glycated, at least under experimental conditions. In Alzheimer's disease, glycation of amyloid ß peptide exacerbates its toxicity and contributes to neurodegeneration. Recent studies establish diabetes mellitus as a risk factor for several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, the mechanisms underlying this connection remain unclear. We hypothesize that hyperglycemia might play an important role in the development of these disorders, possibly by also inducing protein glycation and thereby dysfunction, aggregation, and deposition. Here, we explore protein glycation as a common player in Parkinson's and Alzheimer's diseases and propose it may constitute a novel target for the development of strategies for neuroprotective therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society.

Isostructural Re(I)/(99m)Tc(I) tricarbonyl complexes for cancer theranostics.

Merging classical organic anticancer drugs with metal-based compounds in one single molecule offers the possibility of exploring new approaches for cancer theranostics, i.e. the combination of diagnostic and therapeutic modalities. For this purpose, we have synthesized and biologically evaluated a series of Re(I)/(99m)Tc(I) tricarbonyl complexes (Re1­Re4 and Tc1­Tc4, respectively) stabilized by a cysteamine-based (N,S,O) chelator and containing 2-(4'-aminophenyl)benzothiazole pharmacophores. With the exception of Re1, all the Re complexes have shown a moderate cytotoxicity in MCF7 and PC3 cancer cells (IC50 values in the 15.9­32.1 µM range after 72 h of incubation). The cytotoxic activity of the Re complexes is well correlated with cellular uptake that was quantified using the isostructural (99m)Tc congeners. There is an augmented cytotoxic effect for Re3 and Re4 (versusRe1 and Re2), and the highest cellular uptake for Tc3 and Tc4, which display a long ether-containing linker to couple the pharmacophore to the (N,S,O)-chelator framework. Moreover, fluorescence microscopy clearly confirmed the cytosolic accumulation of the most cytotoxic compound (Re3). Biodistribution studies of Tc1­Tc4 in mice confirmed that these moderately lipophilic complexes (logDo/w = 1.95­2.32) have a favorable bioavailability. Tc3 and Tc4 presented a faster excretion, as they undergo metabolic transformations, in contrast to complexes Tc1 and Tc2. In summary, our results show that benzothiazole-containing Re(I)/(99m)Tc(I) tricarbonyl complexes stabilized by cysteamine-based (N,S,O)-chelators have potential to be further applied in the design of new tools for cancer theranostics.

Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation.

Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of α-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposure to a-syn oligomers drives the increase of glutamatergic synaptic transmission, preventing further potentiation by physiological stimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies.

Heat-mediated enrichment of α-synuclein from cells and tissue for assessing post-translational modifications.

α-Synuclein (α-syn) is the major component of Lewy bodies, a pathological hallmark of Parkinson's disease and other synucleinopathies. The characterization of α-syn post-translational modifications (PTMs), thought to interfere with its aggregation propensity and cellular signaling, has been limited by the availability of extraction methods of endogenous protein from cells and tissues, and by the availability of antibodies toward α-syn PTMs. Here, by taking advantage of α-syn thermostability, we applied a method to achieve high enrichment of soluble α-syn both from cultured cells and brain tissues followed by proteomics analysis. Using this approach, we obtained 98% α-syn sequence coverage in a variety of model systems, including a transgenic mouse model of PD, and validated the strategy by identifying previously described PTMs such as phosphorylation and N-terminal acetylation. Our findings demonstrate that this procedure overcomes existing technical limitations and can be used to facilitate the systematic study of α-syn PTMs, thereby enabling the clarification of their role under physiological and pathological conditions. Ultimately, this approach may enable the development of novel biomarkers and strategies for therapeutic intervention in synucleinopathies.

Unveiling new secrets in Parkinson's disease: The glycatome.

We are witnessing a considerable increase in the incidence of Parkinson's disease (PD), which may be due to the general ageing of the population. While there is a plethora of therapeutic strategies for this disease, they still fail to arrest disease progression as they do not target and prevent the neurodegenerative process. The identification of disease-causing mutations allowed researchers to better dissect the underlying causes of this disease, highlighting, for example, the pathogenic role of alpha-synuclein. However, most PD cases are sporadic, which is making it hard to unveil the major causative mechanisms of this disease. In the recent years, epidemiological evidence suggest that type-2 diabetes mellitus (T2DM) individuals have higher risk and worst outcomes of PD, allowing to raise the hypothesis that some dysregulated processes in T2DM may contribute or even trigger the neurodegenerative process in PD. One major consequence of T2DM is the unprogrammed reaction between sugars, increased in T2DM, and proteins, a reaction named glycation. Pre-clinical reports show that alpha-synuclein is a target of glycation, and glycation potentiates its pathogenicity which contributes for the neurodegenerative process. Moreover, it triggers, anticipates, or aggravates several PD-like motor and non-motor complications. A given profile of proteins are differently glycated in diseased conditions, altering the brain proteome and leading to brain dysfunction and neurodegeneration. Herein we coin the term Glycatome as the profile of glycated proteins. In this review we report on the mechanisms underlying the association between T2DM and PD, with particular focus on the impact of protein glycation.

Dysmetabolism and Neurodegeneration: Trick or Treat?

Accumulating evidence suggests the existence of a strong link between metabolic syndrome and neurodegeneration. Indeed, epidemiologic studies have described solid associations between metabolic syndrome and neurodegeneration, whereas animal models contributed for the clarification of the mechanistic underlying the complex relationships between these conditions, having the development of an insulin resistance state a pivotal role in this relationship. Herein, we review in a concise manner the association between metabolic syndrome and neurodegeneration. We start by providing concepts regarding the role of insulin and insulin signaling pathways as well as the pathophysiological mechanisms that are in the genesis of metabolic diseases. Then, we focus on the role of insulin in the brain, with special attention to its function in the regulation of brain glucose metabolism, feeding, and cognition. Moreover, we extensively report on the association between neurodegeneration and metabolic diseases, with a particular emphasis on the evidence observed in animal models of dysmetabolism induced by hypercaloric diets. We also debate on strategies to prevent and/or delay neurodegeneration through the normalization of whole-body glucose homeostasis, particularly via the modulation of the carotid bodies, organs known to be key in connecting the periphery with the brain.

Glycation modulates glutamatergic signaling and exacerbates Parkinson's disease-like phenotypes.

Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson's disease (PD). Interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction is a contributing factor in synucleinopathies. Here, we dissected the impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain. We found that MGO-glycation potentiates motor, cognitive, olfactory, and colonic dysfunction in aSyn transgenic (Thy1-aSyn) mice that received a single dose of MGO via intracerebroventricular injection. aSyn accumulates in the midbrain, striatum, and prefrontal cortex, and protein glycation is increased in the cerebellum and midbrain. SWATH mass spectrometry analysis, used to quantify changes in the brain proteome, revealed that MGO mainly increase glutamatergic-associated proteins in the midbrain (NMDA, AMPA, glutaminase, VGLUT and EAAT1), but not in the prefrontal cortex, where it mainly affects the electron transport chain. The glycated proteins in the midbrain of MGO-injected Thy1-aSyn mice strongly correlate with PD and dopaminergic pathways. Overall, we demonstrated that MGO-induced glycation accelerates PD-like sensorimotor and cognitive alterations and suggest that the increase of glutamatergic signaling may underly these events. Our study sheds new light into the enhanced vulnerability of the midbrain in PD-related synaptic dysfunction and suggests that glycation suppressors and anti-glutamatergic drugs may hold promise as disease-modifying therapies for synucleinopathies.

The sour side of neurodegenerative disorders: the effects of protein glycation.

Neurodegenerative diseases are associated with the misfolding and deposition of specific proteins, either intra- or extracellularly in the nervous system. Although familial mutations play an important role in protein misfolding and aggregation, the majority of cases of neurodegenerative diseases are sporadic, suggesting that other factors must contribute to the onset and progression of these disorders. Post-translational modifications are known to influence protein structure and function. Some of these modifications might affect proteins in detrimental ways and lead to their misfolding and accumulation. Reducing sugars play important roles in modifying proteins, forming advanced glycation end-products (AGEs) in a non-enzymatic process named glycation. Several proteins linked to neurodegenerative diseases, such as amyloid beta, tau, prions and transthyretin, were found to be glycated in patients, and this is thought to be associated with increased protein stability through the formation of crosslinks that stabilize protein aggregates. Moreover, glycation may be responsible, via the receptor for AGE (RAGE), for an increase in oxidative stress and inflammation through the formation of reactive oxygen species and the induction of NF-kappaB. Therefore, it is essential to unravel the molecular mechanisms underlying protein glycation to understand their role in neurodegeneration. Here, we reviewed the role of protein glycation in the major neurodegenerative disorders and highlight the potential value of protein glycation as a biomarker or target for therapeutic intervention.

Synthesis and in vitro evaluation of fluorinated styryl benzazoles as amyloid-probes.

The formation of proteinaceous aggregates is a pathognomonic hallmark of several neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. To date, the final diagnostic for these diseases can only be achieved by immunostaining of post-mortem brain tissues with the commonly used congo red and Thioflavin T/S amyloid-dyes. The interest in developing amyloid-avid radioprobes to be used for protein aggregates imaging by positron emission tomography has grown substantialy, due to the promise in assisting diagnosis of these disorders. To this purpose, the present work describes the synthesis and characterization of four novel fluorinated styryl benzazole derivatives 1-4 by means of the Wittig reaction, as well as their in vitro evaluation as amyloid-probing agents. All compounds were obtained as mixtures of geometric E and Z isomers, with the preferable formation of the E isomer. Photoisomerization reactions allowed for the maximization of the minor Z isomers. The authentic 1-4E/Z isomers were isolated after purification by column chromatography under dark conditions. Profiting from the fluorescence properties of the different geometric isomers of 1-4, their binding affinities towards amyloid fibrils of insulin, α-synuclein and ß-amyloid peptide were also measured. These compounds share similarities with Thioflavin T, interacting specifically with fibrillary species with a red-shift in the excitation wavelengths along with an increase in the fluorescence emission intensity. Apparent binding constants were determined and ranged between 1.22 and 23.96 µM(-1). The present data suggest that the novel fluorinated styryl benzazole derivatives may prove useful for the design of (18)F-labeled amyloid radioprobes.

The Neuroprotective Action of Amidated-Kyotorphin on Amyloid ß Peptide-Induced Alzheimer's Disease Pathophysiology.

Kyotorphin (KTP, l-tyrosyl-l-arginine) is an endogenous dipeptide initially described to have analgesic properties. Recently, KTP was suggested to be an endogenous neuroprotective agent, namely for Alzheimer's disease (AD). In fact, KTP levels were shown to be decreased in the cerebrospinal fluid of patients with AD, and recent data showed that intracerebroventricular (i.c.v.) injection of KTP ameliorates memory impairments in a sporadic rat model of AD. However, this administration route is far from being a suitable therapeutic strategy. Here, we evaluated if the blood-brain permeant KTP-derivative, KTP-NH2, when systemically administered, would be effective in preventing memory deficits in a sporadic AD animal model and if so, which would be the synaptic correlates of that action. The sporadic AD model was induced in male Wistar rats through i.c.v. injection of amyloid ß peptide (Aß). Animals were treated for 20 days with KTP-NH2 (32.3 mg/kg, intraperitoneally (i.p.), starting at day 3 after Aß administration) before memory testing (Novel object recognition (NOR) and Y-maze (YM) tests). Animals were then sacrificed, and markers for gliosis were assessed by immunohistochemistry and Western blot analysis. Synaptic correlates were assessed by evaluating theta-burst induced long term potentiation (LTP) of field excitatory synaptic potentials (fEPSPs) recorded from hippocampal slices and cortical spine density analysis. In the absence of KTP-NH2 treatment, Aß-injected rats had clear memory deficits, as assessed through NOR or YM tests. Importantly, these memory deficits were absent in Aß-injected rats that had been treated with KTP-NH2, which scored in memory tests as control (sham i.c.v. injected) rats. No signs of gliosis could be detected at the end of the treatment in any group of animals. LTP magnitude was significantly impaired in hippocampal slices that had been incubated with Aß oligomers (200 nM) in the absence of KTP-NH2. Co-incubation with KTP-NH2 (50 nM) rescued LTP toward control values. Similarly, Aß caused a significant decrease in spine density in cortical neuronal cultures, and this was prevented by co-incubation with KTP-NH2 (50 nM). In conclusion, the present data demonstrate that i.p. KTP-NH2 treatment counteracts Aß-induced memory impairments in an AD sporadic model, possibly through the rescuing of synaptic plasticity mechanisms.

Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose.

Cell-to-cell propagation of aggregated alpha synuclein (aSyn) has been suggested to play an important role in the progression of alpha synucleinopathies. A critical step for the propagation process is the accumulation of extracellular aSyn within recipient cells. Here, we investigated the trafficking of distinct exogenous aSyn forms and addressed the mechanisms influencing their accumulation in recipient cells. The aggregated aSyn species (oligomers and fibrils) exhibited more pronounced accumulation within recipient cells than aSyn monomers. In particular, internalized extracellular aSyn in the aggregated forms was able to seed the aggregation of endogenous aSyn. Following uptake, aSyn was detected along endosome-to-lysosome and autophagosome-to-lysosome routes. Intriguingly, aggregated aSyn resulted in lysosomal activity impairment, accompanied by the accumulation of dilated lysosomes. Moreover, analysis of autophagy-related protein markers suggested decreased autophagosome clearance. In contrast, the endocytic pathway, proteasome activity, and mitochondrial homeostasis were not substantially affected in recipient cells. Our data suggests that extracellularly added aggregated aSyn primarily impairs lysosomal activity, consequently leading to aSyn accumulation within recipient cells. Importantly, the autophagy inducer trehalose prevented lysosomal alterations and attenuated aSyn accumulation within aSyn-exposed cells. Our study underscores the importance of lysosomes for the propagation of aSyn pathology, thereby proposing these organelles as interventional targets.