Oxidative stress-induced phosphorylation of JIP4 regulates lysosomal positioning in coordination with TRPML1 and ALG2.

Retrograde transport of lysosomes is recognised as a critical autophagy regulator. Here, we found that acrolein, an aldehyde that is significantly elevated in Parkinson's disease patient serum, enhances autophagy by promoting lysosomal clustering around the microtubule organising centre via a newly identified JIP4-TRPML1-ALG2 pathway. Phosphorylation of JIP4 at T217 by CaMK2G in response to Ca2+ fluxes tightly regulated this system. Increased vulnerability of JIP4 KO cells to acrolein indicated that lysosomal clustering and subsequent autophagy activation served as defence mechanisms against cytotoxicity of acrolein itself. Furthermore, the JIP4-TRPML1-ALG2 pathway was also activated by H2 O2 , indicating that this system acts as a broad mechanism of the oxidative stress response. Conversely, starvation-induced lysosomal retrograde transport involved both the TMEM55B-JIP4 and TRPML1-ALG2 pathways in the absence of the JIP4 phosphorylation. Therefore, the phosphorylation status of JIP4 acts as a switch that controls the signalling pathways of lysosoma l distribution depending on the type of autophagy-inducing signal.

Pathogenic Potential of Eomesodermin-Expressing T-Helper Cells in Neurodegenerative Diseases.

Eomesodermin-expressing (Eomes+) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes+ Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes+ Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes+ Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes+ Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024;95:1093-1098.

JNK-interacting protein 4 is a central molecule for lysosomal retrograde trafficking.

Lysosomal positioning is an important factor in regulating cellular responses, including autophagy. Because proteins encoded by disease-responsible genes are involved in lysosomal trafficking, proper intracellular lysosomal trafficking is thought to be essential for cellular homeostasis. In the past few years, the mechanisms of lysosomal trafficking have been elucidated with a focus on adapter proteins linking motor proteins to lysosomes. Here, we outline recent findings on the mechanisms of lysosomal trafficking by focusing on adapter protein c-Jun NH2 -terminal kinase-interacting protein (JIP) 4, which plays a central role in this process, and other JIP4 functions and JIP family proteins. Additionally, we discuss neuronal diseases associated with aberrance in the JIP family protein. Accumulating evidence suggests that chemical manipulation of lysosomal positioning may be a therapeutic approach for these neuronal diseases.

Extracellular vesicles contain filamentous alpha-synuclein and facilitate the propagation of Parkinson's pathology.

Parkinson's disease (PD) is characterized by the pathological deposition of a-synuclein (a-syn) inclusions, known as Lewy bodies/neurites. Emerging evidence suggests that extracellular vesicles (EVs) play a role in facilitating the spreading of Lewy pathology between the peripheral nervous system and the central nervous system. We analyzed serum EVs obtained from patients with PD (n = 142), multiple system atrophy (MSA) (n = 18), progressive supranuclear palsy (PSP) (n = 28), rapid eye movement sleep behavior disorder (n = 31), and controls (n = 105). While we observed a significant reduction in the number of EVs in PD compared to controls (p = 0.006), we also noted a substantial increase in filamentous α-synuclein within EVs in PD compared to controls (p < 0.0001), MSA (0.012), and PSP (p = 0.03). Further analysis unveiled the role of EVs in facilitating the transmission of filamentous α-synuclein between neurons and from peripheral blood to the CNS. These findings highlight the potential utility of serum α-synuclein filaments within EVs as diagnostic markers for synucleinopathies and underscore the significance of EVs in promoting the dissemination of filamentous α-synuclein throughout the entire body.

Systemic Metabolic Alteration Dependent on the Thyroid-Liver Axis in Early PD.

OBJECTIVE: Parkinson's disease (PD) is a common neurodegenerative disease characterized by initial involvement of the olfactory bulb/amygdala or autonomic nerves followed by nigral degeneration. Although autonomic innervation strictly regulates multiorgan systems, including endocrine functions, circulation, and digestion, how dysautonomia in PD affects systemic metabolism has not been identified. In this study, we tried to estimate the pathogenic linkage of PD by nuclear medicine techniques, trans-omic analysis of blood samples, and cultured cell experiments. METHODS: Thyroid mediastinum ratio of 123 I-metaiodobenzylguanidine (MIBG) scintigraphy was measured in 1,158 patients with PD. Furthermore, serum exosome miRNA transcriptome analysis and plasma metabolome analysis followed by trans-omic analysis were performed in patients with de novo PD and age-matched healthy control persons. Additionally, thyroid hormone was administered to skeletal muscle and liver derived cells to evaluate the effect of hypothyroidism for these organs. RESULTS: Sympathetic denervation of thyroid correlating with its cardiac denervation was confirmed in 1,158 patients with PD by MIBG scintigraphy. Among patients with drug-naïve PD, comprehensive metabolome analysis revealed decreased levels of thyroxine and insufficient fatty acid ß-oxidation, which positively correlate with one another. Likewise, both plasma metabolome data and transcriptome data of circulating exosomal miRNAs, revealed specific enrichment of the peroxisome proliferator-activated receptor (PPARα) axis. Finally, association of thyroid hormone with PPARα-dependent ß-oxidation regulation was confirmed by in vitro experiments. INTERPRETATION: Our findings suggest that interorgan communications between the thyroid and liver are disorganized in the early stage of PD, which would be a sensitive diagnostic biomarker for PD. ANN NEUROL 2023;93:303-316.

Astrocytes Protect Human Dopaminergic Neurons from α-Synuclein Accumulation and Propagation.

The pathologic hallmark of Parkinson's disease is the accumulation of α-synuclein-containing Lewy bodies/neurites almost exclusively in neurons, and rarely in glial cells. However, emerging evidence suggests that glia such as astrocytes play an important role in the development of α-synuclein pathology. Using induced pluripotent stem-derived dopaminergic neurons and astrocytes from healthy subjects and patients carrying mutations in lysosomal ATP13A2, a monogenic form of synucleinopathy, we found that astrocytes rapidly internalized α-synuclein, and exhibited higher lysosomal degradation rates compared with neurons. Moreover, coculturing astrocytes and neurons led to decreased accumulation of α-synuclein in neurons and consequently diminished interneuronal transfer of α-synuclein. These protective functions of astrocytes were attenuated by ATP13A2 deficiency, suggesting that the loss of ATP13A2 function in astrocytes at least partially contributes to neuronal α-synuclein pathology. Together, our results highlight the importance of lysosomal function in astrocytes in the pathogenesis of synucleinopathies.SIGNIFICANCE STATEMENT While most neurodegenerative disorders are characterized by the accumulation of aggregated mutant proteins exclusively in neurons, the contribution of glial cells in this process remains poorly explored. Here, we demonstrate that astrocytes contribute to the removal of extracellular α-synuclein and that disruption of this pathway caused by mutations in the Parkinson's disease-linked gene ATP13A2 result in α-synuclein accumulation in human dopaminergic neurons. We found that astrocytes also protect neurons from α-synuclein propagation, whereas ATP13A2 deficiency in astrocytes compromises this protective function. These results highlight astrocyte-mediated α-synuclein clearance as a potential therapeutic target in disorders characterized by the accumulation of α-synuclein, including Parkinson's disease.

Intrajejunal Infusion of Levodopa/Carbidopa for Advanced Parkinson's Disease: A Systematic Review.

Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open-label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%-26%) commonly relate to device-related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well-controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Randomized double-blind placebo-controlled trial of hydrogen inhalation for Parkinson's disease: a pilot study.

BACKGROUND: Oxidative stress is involved in the progression of Parkinson's disease (PD). Recent studies have confirmed that molecular hydrogen (H2) functions as a highly effective antioxidant in animal models of PD. A placebo-controlled, randomized, double-blind, parallel-group clinical pilot study was conducted to assess the efficacy of hydrogen gas inhalation in Japanese patients with PD on treatment with levodopa. METHODS: Twenty participants fulfilling the Movement Disorder Society criteria were enrolled. Participants inhaled 6.5 (0.1) vol% hydrogen gas in 2 L/min of mixed air or placebo air for 16 weeks, twice a day for 1 h. RESULTS: Five participants were excluded due to deviation from the protocol of the total duration of inhalation < 112 h. No significant differences were seen in the change in the total Movement Disorder Society Unified Parkinson's Disease Rating Scale score from baseline to the 16th week between the group that inhaled hydrogen gas and the group that inhaled placebo air (Mann-Whitney U test, p > 0.05). No adverse events were seen. The compliance to the protocol-based duration of inhalation time in all participants decreased with the elderly participants, the higher daily dose of levodopa, and the higher PDQ-39 items on emotions (n = 20, p < 0.05). CONCLUSION: This pilot study revealed that the inhalation of molecular hydrogen gas was safe, but did not show any beneficial effects in patients with PD. TRIAL REGISTRATION: UMIN ID: 000,039,217 (October 6, 2018).

Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is characterized as a chronic and progressive neurodegenerative disorder, and the deposition of specific protein aggregates of α-synuclein, termed Lewy bodies, is evident in multiple brain regions of PD patients. Although there are several available medications to treat PD symptoms, these medications do not prevent the progression of the disease. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with the pathogenesis of PD. Here we found that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neurotoxicity in the mouse striatum was attenuated by subsequent repeated administration of TPPU, a potent sEH inhibitor. Furthermore, deletion of the sEH gene protected against MPTP-induced neurotoxicity, while overexpression of sEH in the striatum significantly enhanced MPTP-induced neurotoxicity. Moreover, the expression of the sEH protein in the striatum from MPTP-treated mice or postmortem brain samples from patients with dementia of Lewy bodies (DLB) was significantly higher compared with control groups. Interestingly, there was a positive correlation between sEH expression and phosphorylation of α-synuclein in the striatum. Oxylipin analysis showed decreased levels of 8,9-epoxy-5Z,11Z,14Z-eicosatrienoic acid in the striatum of MPTP-treated mice, suggesting increased activity of sEH in this region. Interestingly, the expression of sEH mRNA in human PARK2 iPSC-derived neurons was higher than that of healthy control. Treatment with TPPU protected against apoptosis in human PARK2 iPSC-derived dopaminergic neurons. These findings suggest that increased activity of sEH in the striatum plays a key role in the pathogenesis of neurodegenerative disorders such as PD and DLB. Therefore, sEH may represent a promising therapeutic target for α-synuclein-related neurodegenerative disorders.

BRUP-1, an intracellular bilirubin modulator, exerts neuroprotective activity in a cellular Parkinson's disease model.

Bilirubin, the end product of heme redox metabolism, has cytoprotective properties and is an essential metabolite associated with cardiovascular disease, inflammatory bowel disease, type 2 diabetes, and neurodegenerative diseases including Parkinson's disease (PD). PD is characterized by progressive degeneration of nigral dopaminergic neurons and is associated with elevated oxidative stress due to mitochondrial dysfunction. In this study, using a ratiometric bilirubin probe, we revealed that the mitochondrial inhibitor, rotenone, which is widely used to create a PD model, significantly decreased intracellular bilirubin levels in HepG2 cells. Chemical screening showed that BRUP-1 was a top hit that restored cellular bilirubin levels that were lowered by rotenone. We found that BRUP-1 up-regulated the expression level of heme oxygenase-1 (HO-1), one of the rate-limiting enzyme of bilirubin production via nuclear factor erythroid 2-related factor 2 (Nrf2) activation. In addition, we demonstrated that this Nrf2 activation was due to a direct inhibition of the interaction between Nrf2 and Kelch-like ECH-associated protein 1 (Keap1) by BRUP-1. Both HO-1 up-regulation and bilirubin restoration by BRUP-1 treatment were significantly abrogated by Nrf2 silencing. In neuronal PC12D cells, BRUP-1 also activated the Nrf2-HO-1 axis and increased bilirubin production, resulted in the suppression of neurotoxin-induced cell death, reactive oxygen species production, and protein aggregation, which are hallmarks of PD. Furthermore, BRUP-1 showed neuroprotective activity against rotenone-treated neurons derived from induced pluripotent stem cells. These findings provide a new member of Keap1-Nrf2 direct inhibitors and suggest that chemical modulation of heme metabolism using BRUP-1 may be beneficial for PD treatment.

A metabolic profile of polyamines in parkinson disease: A promising biomarker.

OBJECTIVE: Aging is the highest risk factor for Parkinson disease (PD). Under physiological conditions, spermidine and spermine experimentally enhance longevity via autophagy induction. Accordingly, we evaluated the ability of each polyamine metabolite to act as an age-related, diagnostic, and severity-associated PD biomarker. METHODS: Comprehensive metabolome analysis of plasma was performed in Cohort A (controls, n = 45; PD, n = 145), followed by analysis of 7 polyamine metabolites in Cohort B (controls, n = 49; PD, n = 186; progressive supranuclear palsy, n = 19; Alzheimer disease, n = 23). Furthermore, 20 patients with PD who were successively examined within Cohort B were studied using diffusion tensor imaging (DTI). Association of each polyamine metabolite with disease severity was assessed according to Hoehn and Yahr stage (H&Y) and Unified Parkinson's Disease Rating Scale motor section (UPDRS-III). Additionally, the autophagy induction ability of each polyamine metabolite was examined in vitro in various cell lines. RESULTS: In Cohort A, N8-acetylspermidine and N-acetylputrescine levels were significantly and mildly elevated in PD, respectively. In Cohort B, spermine levels and spermine/spermidine ratio were significantly reduced in PD, concomitant with hyperacetylation. Furthermore, N1,N8-diacetylspermidine levels had the highest diagnostic value, and correlated with H&Y, UPDRS-III, and axonal degeneration quantified by DTI. The spermine/spermidine ratio in controls declined with age, but was consistently suppressed in PD. Among polyamine metabolites, spermine was the strongest autophagy inducer, especially in SH-SY5Y cells. No significant genetic variations in 5 genes encoding enzymes associated with spermine/spermidine metabolism were detected compared with controls. INTERPRETATION: Spermine synthesis and N1,N8-diacetylspermidine may respectively be useful diagnostic and severity-associated biomarkers for PD. ANN NEUROL 2019;86:251-263.

Shared Metabolic Profile of Caffeine in Parkinsonian Disorders.

OBJECTIVE: The objective of this study was to determine comprehensive metabolic changes of caffeine in the serum of patients with parkinsonian disorders including Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) and to compare this with healthy control serum. METHODS: Serum levels of caffeine and its 11 downstream metabolites from independent double cohorts consisting of PD (n = 111, 160), PSP (n = 30, 19), MSA (n = 23, 17), and healthy controls (n = 43, 31) were examined by liquid chromatography-mass spectrometry. The association of each metabolite with clinical parameters and medication was investigated. Mutations in caffeine-associated genes were investigated by direct sequencing. RESULTS: A total of 9 metabolites detected in more than 50% of participants in both cohorts were decreased in 3 parkinsonian disorders compared with healthy controls without any significant association with age at sampling, sex, or disease severity (Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale motor section) in PD, and levodopa dose or levodopa equivalent dose in PSP and MSA. Of the 9 detected metabolites, 8 in PD, 5 in PSP, and 3 in MSA were significantly decreased in both cohorts even after normalizing to daily caffeine consumption. No significant genetic variations in CYP1A2 or CYP2E1 were detected when compared with controls. CONCLUSION: Serum caffeine metabolic profiles in 3 parkinsonian diseases show a high level of overlap, indicative of a common potential mechanism such as caffeine malabsorption from the small intestine, hypermetabolism, increased clearance of caffeine, and/or reduced caffeine consumption. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

NDP52 interacts with mitochondrial RNA poly(A) polymerase to promote mitophagy.

Parkin-mediated mitophagy is a quality control pathway that selectively removes damaged mitochondria via the autophagic machinery. Autophagic receptors, which interact with ubiquitin and Atg8 family proteins, contribute to the recognition of damaged mitochondria by autophagosomes. NDP52, an autophagy receptor, is required for autophagic engulfment of damaged mitochondria during mitochondrial uncoupler treatment. The N-terminal SKICH domain and C-terminal zinc finger motif of NDP52 are both required for its function in mitophagy. While the zinc finger motif contributes to poly-ubiquitin binding, the function of the SKICH domain remains unclear. Here, we show that NDP52 interacts with mitochondrial RNA poly(A) polymerase (MTPAP) via the SKICH domain. During mitophagy, NDP52 invades depolarized mitochondria and interacts with MTPAP dependent on the proteasome but independent of ubiquitin binding. Loss of MTPAP reduces NDP52-mediated mitophagy, and the NDP52-MTPAP complex attracts more LC3 than NDP52 alone. These results indicate that NDP52 and MTPAP form an autophagy receptor complex, which enhances autophagic elimination of damaged mitochondria.

Metabolomic analysis revealed mitochondrial dysfunction and aberrant choline metabolism in MPP+-exposed SH-SY5Y cells.

1-Methyl-4-phenylpyridinium (MPP+)-treated human neuroblastoma SH-SY5Y cells have been generally accepted as a cellular model for Parkinson's disease. To understand comprehensive metabolic disturbances in this model, both cell lysates and culture supernatants were subjected to metabolomic analysis. As expected from the fact that MPP+ inhibits mitochondrial complex I, a metabolic shift from mitochondrial oxidative phosphorylation to glycolysis was indicated by an increase in extracellular lactic acid and a parallel depletion of pyruvic acid. In cell lysates, the metabolic shift was supported by consistent decreases in TCA cycle intermediates. Metabolomic analysis also revealed aberrant choline metabolism. Choline in the culture supernatant was elevated 8.5- and 17-fold by 30 and 300 µM MPP+ exposure, respectively; therefore, extracellular choline might be a metabolic biomarker for Parkinson's disease.

Neuroprotective effects of memantine via enhancement of autophagy.

INTRODUCTION: Chemical intervention of autophagy has been investigated in clinical trials for various age-related conditions such as sarcopenia and neurodegeneration. However, at present, no autophagy inducer has been established as a disease-modifying agent against neurodegenerative diseases. METHODS: We screened a library consisting of 796 medicines clinically approved (in Japan) for autophagy enhancers as potential neurodegeneration therapeutics using HeLa cells stably expressing green fluorescent protein-microtubule-associated protein light chain 3 (GFP-LC3) followed by an analysis of the molecular mechanisms using various neuronal models. RESULTS: The primary screening identified 152 hits in a static cellular state. A widely available Alzheimer's disease drug, memantine, which antagonizes N-Methyl-d-aspartate receptor (NMDAR), was one of the hits. Memantine increased the levels of LC3-II in a dose-dependent and time-dependent manner, and upregulated autophagic flux. In addition, the pharmacological effects of memantine on autophagy were independent of mTORC1 activity and NMDAR activation. Furthermore, a VPS34 inhibitor suppressed the memantine-induced LC3-II upregulation, suggesting that memantine may affect VPS34 complex activity. Notably, intracellular Huntington's disease-specific aggregates of elongated huntingtin, a well-established autophagy substrate, were significantly decreased by memantine. In addition, memantine enhanced elimination of degraded mitochondrial in neurons derived from induced pluripotent stem cells of PARK2 or PARK6 patients, who exhibited defective PINK1/parkin-mediated mitophagy, suggests that memantine accelerated the clearance of damaged mitochondria. CONCLUSION: These findings indicate that memantine may be beneficial for the treatment of neurodegeneration characterized by the abnormal accumulation of autophagy or mitophagy substrates.

Ethambutol neutralizes lysosomes and causes lysosomal zinc accumulation.

Ethambutol is a common medicine used for the treatment of tuberculosis, which can have serious side effects, such as retinal and liver dysfunction. Although ethambutol has been reported to impair autophagic flux in rat retinal cells, the precise molecular mechanism remains unclear. Using various mammalian cell lines, we showed that ethambutol accumulated in autophagosomes and vacuolated lysosomes, with marked Zn(2+) accumulation. The enlarged lysosomes were neutralized and were infiltrated with Zn(2+) accumulations in the lysosomes, with simultaneous loss of acidification. These results suggest that EB neutralizes lysosomes leading to insufficient autophagy, implying that some of the adverse effects associated with EB in various organs may be of this mechanism.

Identification of novel biomarkers for Parkinson's disease by metabolomic technologies.

OBJECTIVE: The pathogenesis of Parkinson's disease (PD) involves complex interactions between environmental and genetic factors. Metabolomics can shed light on alterations in metabolic pathways in many diseases, including neurodegenerative diseases. In the present study, we attempted to elucidate the candidate metabolic pathway(s) associated with PD. METHODS: Serum samples were collected from 35 individuals with idiopathic PD without dementia and 15 healthy age-matched control participants without PD. This analysis used a combination of three independent platforms: ultrahigh-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) optimised for basic species, UPLC/MS/MS optimised for acidic species and gas chromatography/MS (GC/MS). RESULTS: The metabolomic profiles of PD were clearly different from normal controls. PD profiles had significantly lower levels of tryptophan, caffeine and its metabolites, bilirubin and ergothioneine, and significantly higher levels of levodopa metabolites and biliverdin than those of normal controls. Alterations in the bilirubin/biliverdin ratio and ergothioneine can indicate oxidative stress intensity and may suggest elevated oxidative stress and/or insufficient ability for scavenging free radicals, which could contribute to PD pathogenesis. Decreased serum tryptophan level is associated with psychiatric problems in PD. A decrease in serum caffeine levels is consistent with an inverse association of caffeine consumption with development of PD based on past epidemiological studies. CONCLUSIONS: Metabolomic analysis detected biomarkers associated with PD pathogenesis and disease progression. Since critical metabolic biomarkers need to be identified in PD, future studies should include assay validation and replication in independent cohorts.

Preliminary study of substantia nigra analysis by tensorial feature extraction.

PURPOSE: Parkinson disease (PD) is a common progressive neurodegenerative disorder in our ageing society. Early-stage PD biomarkers are desired for timely clinical intervention and understanding of pathophysiology. Since one of the characteristics of PD is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, we propose a feature extraction method for analysing the differences in the substantia nigra between PD and non-PD patients. METHOD: We propose a feature-extraction method for volumetric images based on a rank-1 tensor decomposition. Furthermore, we apply a feature selection method that excludes common features between PD and non-PD. We collect neuromelanin images of 263 patients: 124 PD and 139 non-PD patients and divide them into training and testing datasets for experiments. We then experimentally evaluate the classification accuracy of the substantia nigra between PD and non-PD patients using the proposed feature extraction method and linear discriminant analysis. RESULTS: The proposed method achieves a sensitivity of 0.72 and a specificity of 0.64 for our testing dataset of 66 non-PD and 42 PD patients. Furthermore, we visualise the important patterns in the substantia nigra by a linear combination of rank-1 tensors with selected features. The visualised patterns include the ventrolateral tier, where the severe loss of neurons can be observed in PD. CONCLUSIONS: We develop a new feature-extraction method for the analysis of the substantia nigra towards PD diagnosis. In the experiments, even though the classification accuracy with the proposed feature extraction method and linear discriminant analysis is lower than that of expert physicians, the results suggest the potential of tensorial feature extraction.

Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease.

The autophagy-lysosome pathway plays an indispensable role in the protein quality control by degrading abnormal organelles and proteins including α-synuclein (αSyn) associated with the pathogenesis of Parkinson's disease (PD). However, the activation of this pathway is mainly by targeting lysosomal enzymic activity. Here, we focused on the autophagosome-lysosome fusion process around the microtubule-organizing center (MTOC) regulated by lysosomal positioning. Through high-throughput chemical screening, we identified 6 out of 1200 clinically approved drugs enabling the lysosomes to accumulate around the MTOC with autophagy flux enhancement. We further demonstrated that these compounds induce the lysosomal clustering through a JIP4-TRPML1-dependent mechanism. Among them, the lysosomal-clustering compound albendazole promoted the autophagy-dependent degradation of Triton-X-insoluble, proteasome inhibitor-induced aggregates. In a cellular PD model, albendazole boosted insoluble αSyn degradation. Our results revealed that lysosomal clustering can facilitate the breakdown of protein aggregates, suggesting that lysosome-clustering compounds may offer a promising therapeutic strategy against neurodegenerative diseases characterized by the presence of aggregate-prone proteins.