Roles of neuronal lysosomes in the etiology of Parkinson’s disease

Therapeutic progress in neurodegenerative conditions such as Parkinson’s disease has been hampered by a lack of detailed knowledge of its molecular etiology.The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes involved in the onset of disease.In this respect,the autophagy-lysosome system has emerged in recent years as a strong point of convergence for genetics,genomics,and pathologic indications,spanning both familial and idiopathic Parkinson’s disease.Most,if not all,genes linked to familial disease are involved,in a regulatory capacity,in lysosome function(e.g.,LRRK2,alpha-synuclein,VPS35,Parkin,and PINK1).Moreover,the majority of genomic loci associated with increased risk of idiopathic Parkinson’s cluster in lysosome biology and regulation(GBA as the prime example).Lastly,neuropathologic evidence showed alterations in lysosome markers in autoptic material that,coupled to the alpha-synuclein proteinopathy that defines the disease,strongly indicate an alteration in functionality.In this Brief Review article,I present a personal perspective on the molecular and cellular involvement of lysosome biology in Parkinson’s pathogenesis,aiming at a larger vision on the events underlying the onset of the disease.The attempts at targeting autophagy for therapeutic purposes in Parkinson’s have been mostly aimed at“indiscriminately”enhancing its activity to promote the degradation and elimination of aggregate protein accumulations,such as alpha-synuclein Lewy bodies.However,this approach is based on the assumption that protein pathology is the root cause of disease,while pre-pathology and pre-degeneration dysfunctions have been largely observed in clinical and pre-clinical settings.In addition,it has been reported that unspecific boosting of autophagy can be detrimental.Thus,it is important to understand the mechanisms of specific autophagy forms and,even more,the adjustment of specific lysosome functionalities.Indeed,lysosomes exert fine signaling capacities in addition to their catabolic roles and might participate in the regulation of neuronal and glial cell functions.Here,I discuss hypotheses on these possible mechanisms,their links with etiologic and risk factors for Parkinson’s disease,and how they could be targeted for disease-modifying purposes.

Role of lysosomal trafficking regulator in autophagic lysosome reformation in neurons:a disease perspective

Lysosomes are discrete organelles that act as recycling centers for extracellular and intracellular materials,playing a pivotal role in maintaining cellular homeostasis.Their acidic environment,maintained by numerous hydrolytic enzymes,facilitates substrate degradation.Dysfunction in lysosomal processes can lead to abnormal substrate degradation,significantly impacting cellular homeostasis.High energy-demanding cells,such as post-mitotic neurons,are especially vulnerable to these changes,often resulting in neurological diseases.Autophagy,a conserved catabolic process,requires extensive lysosomal utilization.It plays a key role in removing unnecessary intracellular components,ensuring cellular homeostasis,and promoting cell survival during stress conditions such as starvation,infection,or cellular damage.

Enhancement of lysosome biogenesis as a potential therapeutic approach for neurodegenerative diseases

Millions of people are suffering from Alzheimer’s disease globally,but there is still no effective treatment for this neurodegenerative disease.Thus,novel therapeutic approaches for Alzheimer’s disease are needed,which requires further evaluation of the regulato ry mechanisms of protein aggregate degradation.Lysosomes are crucial degradative organelles that maintain cellular homeostasis.Transcription factor EB-mediated lysosome biogenesis enhances autolysosomedependent degradation,which subsequently alleviates neurodege nerative diseases,including Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease.In this review,we start by describing the key features of lysosomes,including their roles in nutrient sensing and degradation,and their functional impairments in different neurodegenerative diseases.We also explain the mechanisms—especially the post-translational modifications—which impact transcription factor EB and regulate lysosome biogenesis.Next,we discuss strategies for promoting the degradation of toxic protein aggregates.We describe Proteolysis-Ta rgeting Chimera and related technologies for the targeted degradation of specific proteins.We also introduce a group of LYsosome-Enhancing Compounds,which promote transcription factor EB-mediated lysosome biogenesis and improve learning,memory,and cognitive function in APP-PSEN1 mice.In summary,this review highlights the key aspects of lysosome biology,the mechanisms of transcription factor EB activation and lysosome biogenesis,and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.

SIRT1 facilitates amyloid beta peptide degradation by upregulating lysosome number in primary astrocytes

Previous studies have shown that sirtuin 1（SIRT1） reduces the production of neuronal amyloid beta（Aβ） and inhibits the inflammatory response of glial cells, thereby generating a neuroprotective effect against Aβ neurotoxicity in animal models of Alzheimer＇s disease. However, the protective effect of SIRT1 on astrocytes is still under investigation. This study established a time point model for the clearance of Aβ in primary astrocytes. Results showed that 12 hours of culture was sufficient for endocytosis of oligomeric Aβ, and 36 hours sufficient for effective degradation. Immunofluorescence demonstrated that Aβ degradation in primary astrocytes relies on lysosome function. Enzymatic agonists or SIRT1 inhibitors were used to stimulate cells over a concentration gradient. Aβ was co-cultured for 36 hours in medium. Western blot assay results under different conditions revealed that SIRT1 relies on its deacetylase activity to promote intracellular Aβ degradation. The experiment further screened SIRT1 using quantitative proteomics to investigate downstream, differentially expressed proteins in the Aβ degradation pathway and selected the ones related to enzyme activity of SIRT1. Most of the differentially expressed proteins detected are close to the primary astrocyte lysosomal pathway. Immunofluorescence staining demonstrated that SIRT1 relies on its deacetylase activity to upregulate lysosome number in primary astrocytes. Taken together, these findings confirm that SIRT1 relies on its deacetylase activity to upregulate lysosome number, thereby facilitating oligomeric Aβ degradation in primary astrocytes.

KCNJ15 deficiency promotes drug resistance via affecting the function of lysosomes

The altered lysosomal function can induce drug redistribution which leads to drug resistance and poor prognosis for cancer patients.V-ATPase,an ATP-driven proton pump positioned at lysosomal surfaces,is responsible for maintaining the stability of lysosome.Herein,we reported that the potassium voltage-gated channel subfamily J member 15(KCNJ15)protein,which may bind to V-ATPase,can regulate the function of lysosome.The deficiency of KCNJ15 protein in breast cancer cells led to drug aggregation as well as reduction of drug efficacy.The application of the V-ATPase inhibitor could inhibit the binding between KCNJ15 and V-ATPase,contributing to the amelioration of drug resistance.Clinical data analysis revealed that KCNJ15 deficiency was associated with higher histological grading,advanced stages,more metastases of lymph nodes,and shorter disease free survival of patients with breast cancer.KCNJ15 expression level is positively correlated with a high response rate after receiving neoadjuvant chemotherapy.Moreover,we revealed that the small molecule drug CMA/BAF can reverse drug resistance by disrupting the interaction between KCNJ15 and lysosomes.In conclusion,KCNJ15 could be identified as an underlying indicator for drug resistance and survival of breast cancer,which might guide the choice of therapeutic strategies.

Association of Lysosome Associated Protein Transmembrane 4 Beta Gene Polymorphism with the Risk of Pancreatic Cancer

Objective： Lysosome associated protein transmembrane 4 beta （LAPTM4B） was originally identified as a gene in human hepatocellular carcinoma （HCC）. It was successfully cloned by fluorescence differential display, rapid amplification of cDNA ends （RACE） and reverse transcription polymerase chain reaction （RT-PCR）. Previous study showed that the novel gene played an important role in the occurrence, development, migration and prognosis of tumors. Pancreatic cancer is an aggressive malignancy with the majority of patients dying within one year after diagnosis. This study tries to find out the relationship between lysosome associated protein transmembrane 4 beta gene polymorphism and the susceptibility of pancreatic cancer. Methods： A case-control study was conducted in China, including 58 pancreatic cancer cases and 156 healthy controls. Human genomic DNA was used as the template, polymerase chain reaction （PCR） was used to detect the distribution of LAPTM4B genotype. Analyses Odds ratio （OR） and corresponding 95% confidence interval （95%CI） with logistic regression were performed. Results： Two alleles of LAPTM4B generated three kinds of genotypes in population, ＊1/1, ＊1/2, and ＊2/2. The genotype frequency of ＊1/1, ＊1/2 and ＊2/2 in the pancreatic cancer group were 41.4%, 44.8% and 13.8% respectively, which were not significantly different from those of healthy group （47.4%, 42.9%, 9.6%） （P=0.773, P=0.291）. Also the ＊2 allele frequency of LAPTM4B among pancreatic cancer had no significantly difference with the controls （P=0.354）. When compared to the ＊1 allele, the people with ＊2 allele had no increased risk of pancreatic cancer. Conclusion： The gene polymorphism of LAPTM4B may not influence the susceptibility of pancreatic cancer.

Combination of kaempferol and chloroquine induces glioma cell death via expansion and subsequent rupture of lysosomes

OBJECTIVE Chloroquine is considered as a potential chemotherapy and radiotherapy sensitizer,but the anticancer effect of chloroquine alone is limited.Since we found that the flavonoid kaempferol effectively sensitizes glioma cells to chloroquine-mediated cell death,we investigated the underlying mechanisms of glioma cell death induced by the combination of kaempferol and chloroquine.METHODS To examine the effect of kaempferol and/or chloroquine on various glioma cells,cell viability assay using calcein-AM and EthD-1was performed.The changes in the lysosomal structures following treatment with kaempferol and/or chloroquine were observed by electron microscopy and fluorescence microscopy using acridine orange or Lyso-tracker Red.The changes in cathepsin D proteins were analyzed by Western blotting,immunocytochemistry,and fluorescence microscopy using BODIPY FL-pepstatin.RESULTS Treatment with subtoxic doses of chloroquine,when combined with kaempferol,effectively induced cell death in various glioma cells,but not in normal astrocytes.While kaempferol treatment increased the numbers of lysosome,chloroquine treatment increased lysosomal masses.Combined treatment with kaempferol and chloroquine induced the expansion and subsequent rupture of lysosomes,leading to the spillage of the lysosomal contents into the cytosol.We found that while kaemfperol treatment increased the active mature forms of cathepsin D,chloroquine treatment completely blocked the processing of cathepsin D.The processing of cathepsin D was also blocked by the combined treatment,but the activity of cathepsin D,which was released from the lysosomes,was restored.The cell death induced by kaempferol and chloroquine in U251 MG cells was accompanied by mitochondrial dysfunction,ER stress,and DNA damage.CONCLUSION Disruption of lysosomal membrane integrity and a resultant release of lysosomal proteases may critically contribute to the irreparable damage of various organelles and glioma cell death by chloroquine plus kaempferol.

Detection of distribution of copper inside and outside of lysosomes in cultured hepatolenticular degeneration fibroblasts by electron probe X-ray microanalysis

OBJECTIVE: To observe the distribution of copper in the subcellular structure for the understanding of primary pathogenesis of hepatolenticular degeneration (HLD). METHODS: Skin fibroblasts taken from HLD patients were cultured as an in vitro model of HLD, and the control cells taken from healthy volunteers were clutured in the same way. The distribution of copper inside and outside of lysosomes in fibroblasts was detected by quantitative electron probe X-ray microanalysis. The relationship between the subcellular location of copper and the genotype of the patients, and relationship between the distribution of copper and the course of the disease were analyzed. RESULTS: The content of Cu^(2+) inside lysosomes of HLD cells (14.6±2.1 mmol/kg) and of heterozygote cells (11.6±0.6 mmol/kg) was higher than that of normal cells (4.5±1.2 mmol/kg) (P<0.01). The content of Cu^(2+) outside lysosomes of HLD cells (17.5±4.2 mmol/kg) and of heterozygote cells (12.0±0.9 mmol/kg) was higher than that of normal cells (4.7±1.2 mmol/kg) (P<0.01). The distribution of copper in the subcellular structure was correlated with disease courses of HLD patients. With the progression of the disease, more copper was deposited in lysosomes (r=0.85, P<0.01). The content of copper in the diffused cytoplasmic compartment in HLD cells was correlated with that of sulfur (r=0.86, P<0.05), but not in heterozygote and normal cells. CONCLUSIONS: In the early stage of HLD, copper is accumulated outside lysosome, which is paralleled with increase of metallothionein-like proteins (copper and sulfur-binding proteins). With the development of the disease, more copper is deposited inside lysosome than outside lysosome. We conclude that the up-regulation expression of copper and sulfur-binding proteins and copper accumulation in lysosomes may play an important role in lowering the ATP7B gene mutation-induced toxic effects of free copper on the cell.

Anti-sense RNA Inhibits the Expression of Synaptotagmin Ⅱ in RBL-2H3 and Enhances the Exocytosis of Lysosomes in RBL-2H3

Summary: The expression of synaptotagmin Ⅱ(Syt2) in RBL-2H3 (RBL) and its role during exocytosis of RBL was investigated. The expression of Syt2 in RBL was detected by western blot and Syt2 gene was amplified by PCR. The anti-sense full length Syt2 cDNA expression vector was constructed with pEGFP-N1 and transfected into RBL by electroporation, and stable transfectants were selected by using G418. To analyze the role of Syt2 during exocytosis of RBL, the release of cathepsin D was assayed by immunoblotting. The results showed that Syt2 was expressed in RBL. The anti-sense expression vector pEGFP-N1-Syt2-AS was constructed and the sequence of insertion was completely consistent with rat Syt2 (accession number in GeneBank : NM012665). The stable transfectants (RBL-Syt2-AS) were obtained. Western blot showed that RBL-Syt2-AS expressed a lower level of Syt2 (8 % and 10 % of control cells), indicating that the expression of Syt2 in RBL-Syt2-AS was markedly down-regulated by anti-RNA. Compared with control, the release of cathepsin D by RBL-Syt2-AS was increased. It was concluded that Syt2 expressed in RBL and could inhibit exocytosis of lysosomes in RBL.

Concluding Step in Cell Restitution Cycle: ER Transport Vesicles with Sphingolipids in the Outer Leaflet of the Membrane Restore Lysosomes

Restitution of the cell organelles and the membrane implicates serine palmitoyltransferase (SPT) in signal-specific and selective assembly of the transport vesicles. Here, we reveal that SPT, embedded in the outer leaflet (OL) of endoplasmic reticulum (ER), is engaged in the synthesis of ER transport vesicles that recondition cell organelles, and the inner leaflet (IL) SPT in the restitution of the cell membrane. The OL SPT impacts assembly of sphingomyelinase (SMase)—susceptible ER vesicles but not the SMase-resistant and sphingolipid (SPhL) core—carrying vesicles that refurbish the cell membrane. The investigation of the SPT-initiated differences in the placement of SPhL in vesicular membranes by utilizing ER depleted of OL SPT, allows us to conclude that the restitution of endosomal and lysosomal membranes is achieved with the involvement of OL SPT, whereas the IL SPT is involved in formation of the lipid core for glycosphingolipids (GSL) and sphingomyelin (SM) of the apical and basolateral cell membrane. These findings along with our previously published report (Slomiany and Slomiany, Advances in Biological Chemistry, 2013, 3, 275-287), provide a clear distinction between the processes that renovate cell membrane and its organelles from that of the endocytotic cell debridement, and show that vesicles are navigated to the specific organelles and the cell membrane by the biomembrane constituents programmed in ER.

S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3

The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosisinducing activity in various cells of different origins. Here, we present evidence that the underlying molecular mechanisms involve both programmed cell death I （PCD I, apoptosis） and PCD II （autophagy）-like death. Treatment of cells with S100A8/A9 caused the increase of Beclin-1 expression as well as Atgl2-Atg5 formation. S100A8/A9-induced cell death was partially inhibited by the specific PI3-kinase class Ⅲ inhibitor, 3-methyladenine （3-MA）, and by the vacuole H＋-ATPase inhibitor, bafilomycin-A1 （Baf-A1）. S100A8/A9 provoked the translocation of BNIP3, a BH3 only pro-apoptotic Bcl2 family member, to mitochondria. Consistent with this finding, ATM-BNIP3 overexpression partially inhibited S100A8/A9-induced cell death, decreased reactive oxygen species （ROS） generation, and partially pro- tected against the decrease in mitochondrial transmembrane potential in S100A8/A9-treated ceils. In addition, either ATM-BNIP3 overexpression or N-acetyl-L-cysteine co-treatment decreased lysosomal activation in cells treated with S100A8/A9. Our data indicate that S100A8/A9-promoted cell death occurs through the cross-talk of mitochondria and lysosomes via ROS and the process involves BNIP3.

Enhanced lysosome escape mediated by 1,2-dicarboxylic-cyclohexene anhydride-modified poly-L-lysine dendrimer as a gene delivery system

Antisense oligodeoxynucleotide(ASODN)can directly interfere a series of biological events of the target RNA derived from tumor cells through Watson-Crick base pairing,in turn,plays antitumor therapeutic roles.In the study,a novel HIF-1αASODN-loaded nanocomposite was formulated to efficiently deliver gene to the target RNA.The physicochemical properties of nanocomposite were characterized using TEM,FTIR,DLS and zeta potentials.The mean diameter of resulting GEL-DGL-FA-ASODN-DCA nanocomposite was about 170–192 nm,and according to the agarose gel retardation assay,the loading amount of ASODN accounted for 166.7 mg/g.The results of cellular uptake showed that the nanocomposite could specifically target to HepG2 and Hela cells.The cytotoxicity assay demonstrated that the toxicity of vectors was greatly reduced by using DCA to reversibly block the cationic DGL.The subcellular distribution images clearly displayed the lysosomal escape ability of the DCA-modified nanocomposite.In vitro exploration of molecular mechanism indicated that the nanocomposite could inhibit m RNA expression and HIF-1αprotein translation at different levels.In vivo optical images and quantitative assay testified that the formulation accumulated preferentially in the tumor tissue.In vivo antitumor efficacy research confirmed that this nanocomposite had significant antitumor activity and the tumor inhibitory rate was 77.99%.These results manifested that the GEL-DGL-FA-ASODNDCA nanocomposite was promising in gene therapeutics for antitumor by interacting directly with target RNA.

The role of lysosome in regulated necrosis

Lysosome is a ubiquitous acidic organelle fundamental for the turnover of unwanted cellular molecules,particles,and organelles.Currently,the pivotal role of lysosome in regulating cell death is drawing great attention.Over the past decades,we largely focused on how lysosome influences apoptosis and autophagic cell death.However,extensive studies showed that lysosome is also prerequisite for the execution of regulated necrosis(RN).Different types of RN have been uncovered,among which,necroptosis,ferroptosis,and pyroptosis are under the most intensive investigation.It becomes a hot topic nowadays to target RN as a therapeutic intervention,since it is important in many patho/physiological settings and contributing to numerous diseases.It is promising to target lysosome to control the occurrence of RN thus altering the outcomes of diseases.Therefore,we aim to give an introduction about the common factors influencing lysosomal stability and then summarize the current knowledge on the role of lysosome in the execution of RN,especially in that of necroptosis,ferroptosis,and pyroptosis.

Nano-hydroxyapatite accelerates vascular calcification via lysosome impairment and autophagy dysfunction in smooth muscle cells

Vascular calcification(VC)is a common characteristic of aging,diabetes,chronic renal failure,and atherosclerosis.The basic component of VC is hydroxyapatite(HAp).Nano-sized HAp(nHAp)has been identified to play an essential role in the development of pathological calcification of vasculature.However,whether nHAp can induce calcification in vivo and the mechanism of nHAp in the progression of VC remains unclear.We discovered that nHAp existed both in vascular smooth muscle cells(VSMCs)and their extracellular matrix(ECM)in the calcified arteries from patients.Synthetic nHAp had similar morphological and chemical properties as natural nHAp recovered from calcified artery.nHAp stimulated osteogenic differentiation and accelerated mineralization of VSMCs in vitro.Synthetic nHAp could also directly induce VC in vivo.Mechanistically,nHAp was internalized into lysosome,which impaired lysosome vacuolar H+-ATPase for its acidification,therefore blocked autophagic flux in VSMCs.Lysosomal re-acidification by cyclic-3′,5′-adenosine monophosphate(cAMP)significantly enhanced autophagic degradation and attenuated nHAp-induced calcification.The accumulated autophagosomes and autolysosomes were converted into calcium-containing exosomes which were secreted into ECM and accelerated vascular calcium deposit.Inhibition of exosome release in VSMCs decreased calcium deposition.Altogether,our results demonstrated a repressive effect of nHAp on lysosomal acidification,which inhibited autophagic degradation and promoted a conversion of the accumulated autophagic vacuoles into exosomes that were loaded with undissolved nHAp,Ca^(2+),Pi and ALP.These exosomes bud off the plasma membrane,deposit within ECM,and form calcium nodules.Vascular calcification was thus accelerated by nHAP through blockage of autophagic flux in VSMCs.

Nanoscale monitoring of mitochondria and lysosome interactions for drug screening and discover

Technology advances in genomics,proteomics,and metabolomics largely expanded the pool of potential therapeutic targets.Compared with the in vitro setting,cell-based screening assays have been playing a key role in the processes of drug discovery and development.Besides the commonly used strategies based on colorimetric and cell viability,we reason that methods that capture the dynamic cellular events will facilitate optimal hit identification with high sensitivity and specificity.Herein,we propose a live-cell screening strategy using structured illumination microscopy (SIM) combined with an automated cell colocalization analysis software,CellprofilerTM,to screen and discover drugs for mitochondria and lysosomes interaction at a nanoscale resolution in living cells.This strategy quantitatively benchmarks the mitochondria-lysosome interactions such as mitochondria and lysosomes contact (MLC) and mitophagy.The automatic quantitative analysis also resolves fine changes of the mitochondria-lysosome interaction in response to genetic and pharmacological interventions.Super-resolution live-cell imaging on the basis of quantitative analysis opens up new avenues for drug screening and development by targeting dynamic organelle interactions at the nanoscale resolution,which could facilitate optimal hit identification and potentially shorten the cycle of drug discovery.

α-Synuclein aggregation and transmission in Parkinson’s disease: a link to mitochondria and lysosome

The presence of intraneuronal Lewy bodies(LBs) and Lewy neurites(LNs) in the substantia nigra(SN) composed of aggregatedα-synuclein(α-syn) has been recognized as a hallmark of pathological changes in Parkinson’s disease(PD). Numerous studies have shown that aggregated α-syn is necessary for neurotoxicity. Meanwhile, the mitochondrial and lysosomal dysfunctions are associated with α-syn pathogenicity. The hypothesis that α-syn transmission in the human brain contributes to the instigation and progression of PD has provided insights into PD pathology. This review will provide a brief overview of increasing researches that shed light on the relationship of α-syn aggregation with mitochondrial and lysosomal dysfunctions, and highlight recent understanding of α-syn transmission in PD pathology.

Atg5 regulates late endosome and lysosome biogenesis

Autophagy is an evolutionarily conserved lysosome-based degradation process.Atg5 plays a very important role in autophagosome formation.Here we show that Atg5 is required for biogenesis of late endosomes and lysosomes in an autophagy-independent manner.In Atg5 cells,but not in other essential autophagy genes defecting cells,recycling and retrieval of late endosomal components from hybrid organelles are impaired,causing persistent hybrid organelles and defective formation of late endosomes and lysosomes.Defective retrieval of late endosomal components from hybrid organelles resulting from impaired recruitment of a component of V1-ATPase to acidic organelles blocks the pH-dependent retrieval of late endosomal components from hybrid organelles.Lowering the intracellular pH restores late endosome/lysosome biogenesis in Atg5 cells.Our data demonstrate an unexpected role of Atg5 and shed new light on late endosome and lysosome biogenesis.

Recent advances in mitochondria-and lysosomes-targeted small-molecule two-photon fluorescent probes

Mitochondria and lysosomes are essential cellular organelles in most eukaryotic cells by playing the physiological roles to support the normal functions of cells, as well as the life of the whole body. To date,small-molecule fluorescent probes have been considered as one of the vital tools for monitoring and visualizing multiple biological analytes. This review summarized the recent advances in small-molecule two-photon fluorescent probes for metal ions, reactive oxygen species（ROS） and reactive sulfur species（RSS）, and changes inside micro-environment（e.g., p H, viscosity and polarity） in mitochondria and lysosomes, or served as mitotracker and lysotracker with the assistance of two-photon microscopy.

Super-resolution imaging and real-time tracking lysosome in living cells by a fluorescent probe

Lysosomes function as important organelles within cells and their movement associates with diverse biological events, hence the real-time tracking of lysosomal movement is of great significance. However, since most ly so some fluorescent probes suffer from relatively unsatisfactory photo stability,tracking lysosomal movement in real-time remains challenging. Here,we report that a naphthalimide-based fluorescent compound,namely NIMS,is a quite promising probe for ly so some imaging. The visualizing mechanism lies in the selective accumulation of NIMS in lysosomes via a protonation reaction, followed by the fluorescence enhancement due to the interactions of NIMS with proteins. Owing to its high selectivity and good photo stability, NIMS was successfully applied to capture super-resolution fluorescence images of lysosomes. More importantly, real-time tracking of ly so some movement in a single living cell by NIMS was realized with a confocal laser scanning microscope. Surprisingly,even in normal culture conditions, around 2/3 of the captured lysosomes were observed to move within 5 min, indicative of the highly dynamic features of lysosomes. Thus, this probe may facilitate the understanding of the ly so some dynamics in physiologicalor pathological conditions.

Nanomaterials-mediated lysosomal regulation:a robust protein-clearance approach for the treatment of Alzheimer’s disease

Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within the brain.Lysosomes,crucial intracellular organelles responsible for protein degradation,play a key role in maintaining cellular homeostasis.Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases,including Alzheimer’s disease.Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease.Currently,the efficacy of drugs in treating Alzheimer’s disease is limited,with major challenges in drug delivery efficiency and targeting.Recently,nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties.This review aims to provide a comprehensive overview of recent advances in using nanomaterials(polymeric nanomaterials,nanoemulsions,and carbon-based nanomaterials)to enhance lysosomal function in treating Alzheimer’s disease.This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function.In conclusion,this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease.The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.