Search

This review explores diverse infectious etiologies of peripheral nervous system (PNS) dysfunction, spanning sensory and motor neurons, nerves, and associated structures. Progress in viral and bacterial infections reveals multifaceted mechanisms underlying neuropathies, including viral neurotoxicity and immune-mediated responses. Latest diagnostic advances facilitate early PNS complication detection, with ongoing research offering promising treatment avenues. Emerging pathogens like severe acute respiratory syndrome coronavirus 2, Zika virus, and EV-D68 highlight the evolving infectious neuropathy paradigm. Recognizing characteristic patterns and integrating clinical factors are pivotal for precise diagnosis and tailored intervention. Challenges persist in assessment and management due to varied pathogenic mechanisms. Advancements in understanding pathogenesis have improved targeted therapies, yet gaps remain in effective treatments. Ongoing research is crucial for optimizing approaches and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Vasculitic neuropathies are a diverse group of inflammatory polyneuropathies that result from systemic vasculitis (e.g., polyarteritis nodosa, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis), vasculitis resulting from rheumatological disorders (e.g., rheumatoid arthritis and Sjögren's syndrome), paraneoplastic conditions, viruses, and medications. Occasionally, vasculitis is restricted to the peripheral nerves and termed nonsystemic vasculitic neuropathy. Presenting with an acute or subacute onset of painful sensory and motor deficits, ischemia to individual peripheral nerves results in the classic "mononeuritis multiplex" pattern. Over time, overlapping mononeuropathies will result in a symmetrical or asymmetrical sensorimotor axonal polyneuropathy. The diagnosis of vasculitic neuropathies relies on extensive laboratory testing, electrodiagnostic testing, and nerve and/or other tissue biopsy. Treatment consists primarily of immunosuppressant medications such as corticosteroids, cyclophosphamide, rituximab, methotrexate, or azathioprine, in addition to neuropathic pain treatments. Frequently, other specialists such as rheumatologists, pulmonologists, and nephrologists will comanage these complex patients with systemic vasculitis. Prompt recognition of these conditions is imperative, as delays in treatment may result in permanent deficits and even death. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a prevalent neurodegenerative condition for which there are symptomatic treatments but no disease-modifying therapies (DMTs). Extensive research over the years has highlighted the need for a multi-target DMT approach in PD that recognizes the various risk factors and their intricate interplay in contributing to PD-related neurodegeneration. Widespread risk factors, such as emotional stress and metabolic factors, have increasingly become focal points of exploration. Our review aims to summarize interactions between emotional stress and selected key players in metabolism, such as insulin, as potential mechanisms underlying neurodegeneration in PD. [ABSTRACT FROM AUTHOR]

Background: Numerous studies reported a higher prevalence of polyneuropathy (PNP) in patients with Parkinson's disease (PD) compared to the general population. Importantly, PNP symptoms can aggravate both motor and sensory disturbances in PD patients and negatively impact the disease course. Recent analyses indicate distinct PNP patterns in PD. Main text: This review aims to provide an overview of the current insights into etiological factors, diagnostic methods, and management strategies of large fiber neuropathy in PD. Despite the higher prevalence, the causes of PNP in PD are still not fully understood. A genetic predisposition can underlie PNP onset in PD. Main research attention is focused on long-term levodopa exposure which is suggested to increase PNP risk by depletion of methylation cofactors such as vitamin B12 and accumulation of homocysteine that altogether can alter peripheral nerve homeostasis. Beyond a potential "iatrogenic" cause, alpha-synuclein deposition has been detected in sural nerve fibers that could contribute to peripheral neuronal degeneration as part of the systemic manifestation of PD. Whereas mild axonal sensory PNP predominates in PD, a considerable proportion of patients also show motor and upper limb nerve involvement. Intriguingly, a correlation between PNP severity and PD severity has been demonstrated. Therefore, PNP screening involving clinical and instrument-based assessments should be implemented in the clinical routine for early detection and monitoring. Given the etiological uncertainty, therapeutic or preventive options remain limited. Vitamin supplementation and use of catechol-O-methyltransferase-inhibitors can be taken into consideration. Conclusion: PNP is increasingly recognized as a complicating comorbidity of PD patients. Long-term, large-scale prospective studies are required to elucidate the causative factors for the development and progression of PD-associated PNP to optimize treatment approaches. The overall systemic role of "idiopathic" PNP in PD and a putative association with the progression of neurodegeneration should also be investigated further. [ABSTRACT FROM AUTHOR]

Background: While previous research has established an association between inflammatory bowel disease (IBD) and osteoporosis (OP), the nature of this association in different populations remains unclear. Objective: Our study used linkage disequilibriumscores(LDSC) regression analysis and Mendelian randomization(MR) to assess the genetic correlation and causal relationship between IBD and OP in European and East Asian populations. Methods: We performed separate genetic correlation and causal analyses for IBD and OP in European and East Asian populations, used the product of coefficients method to estimate the mediating effect of nutritional status on the causal relationship, and used multi-trait analysis to explore the biological mechanisms underlying the IBD-nutrition-OP causal pathway. Results: Our analysis revealed a significant genetic correlation and causal relationship between IBD and OP in the European population. Conversely, no such correlation or causal relationship was observed in the East Asian population. Mediation analysis revealed a significant mediating effect of nutritional status on the causal pathway between IBD and OP in the European population. Multi-trait analysis of the IBD-nutrition-OP causal pathway identified MFAP2, ATP13A2, SERPINA1, FTO and VCAN as deleterious variants. Conclusion: Our findings establish a genetic correlation and causal relationship between IBD and OP in the European population, with nutritional status playing a crucial mediating role. [ABSTRACT FROM AUTHOR]

Highly reproducible epidemiological evidence shows that type 2 diabetes (T2D) increases the risk and rate of progression of Parkinson's disease (PD), and crucially, the repurposing of certain antidiabetic medications for the treatment of PD has shown early promise in clinical trials, suggesting that the effects of T2D on PD pathogenesis may be modifiable. The high prevalence of T2D means that a significant proportion of patients with PD may benefit from personalized antidiabetic treatment approaches that also confer neuroprotective benefits. Therefore, there is an immediate need to better understand the mechanistic relation between these conditions and the specific molecular pathways affected by T2D in the brain. Although there is considerable evidence that processes such as insulin signaling, mitochondrial function, autophagy, and inflammation are involved in the pathogenesis of both PD and T2D, the primary aim of this review is to highlight the evidence showing that T2D-associated dysregulation of these pathways occurs not only in the periphery but also in the brain and how this may facilitate neurodegeneration in PD. We also discuss the challenges involved in disentangling the complex relationship between T2D, insulin resistance, and PD, as well as important questions for further research. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exerciseinduced insulin sensitivity in the context of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Mood disorders are highly prevalent and heterogenous mental illnesses with devastating rates of mortality and treatment resistance. The molecular basis of those conditions involves complex interplay between genetic and environmental factors. Currently, there are no objective procedures for diagnosis, prognosis and personalization of patients' treatment. There is an urgent need to search for novel molecular targets for biomarkers in mood disorders. Cellular prion protein (PrPc) is infamous for its potential to convert its insoluble form, leading to neurodegeneration in Creutzfeldt-Jacob disease. Meanwhile, in its physiological state, PrPc presents neuroprotective features and regulates neurotransmission and synaptic plasticity. The aim of this study is to integrate the available knowledge about molecular mechanisms underlying the impact of PrPc on the pathophysiology of mood disorders. Our review indicates an important role of this protein in regulation of cognitive functions, emotions, sleep and biological rhythms, and its deficiency results in depressive-like behavior and cognitive impairment. PrPc plays a neuroprotective role against excitotoxicity, oxidative stress and inflammation, the main pathophysiological events in the course of mood disorders. Research indicates that PrPc may be a promising biomarker of cognitive decline. There is an urgent need of human studies to elucidate its potential utility in clinical practice. [ABSTRACT FROM AUTHOR]

The identification of multiple genes linked to Parkinson’s disease (PD) invites the question as to how they may co-operate. We have generated isogenic cell lines that inducibly express either wild-type or a mutant form of the retromer component VPS35 (D620N), which has been linked to PD. This has enabled us to test proposed effects of this mutation in a setting where the relative expression reflects the physiological occurrence. We confirm that this mutation compromises VPS35 association with the WASH complex, but find no defect in WASH recruitment to endosomes, nor in the distribution of lysosomal receptors, cation-independent mannose-6-phosphate receptor and Sortilin. We show VPS35 (D620N) enhances the activity of the Parkinson’s associated kinase LRRK2 towards RAB12 under basal conditions. Furthermore, VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress resulting in enhanced phosphorylation of RABs 10 and 12. By comparing different types of endolysosomal stresses such as the ionophore nigericin and the membranolytic agent L-leucyl-L-leucine methyl ester, we are able to dissociate phospho-RAB accumulation from membrane rupture. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases involve the progressive dysfunction and loss of neurons in the central nervous system and thus present a significant challenge due to the absence of effective therapies for halting or reversing their progression. Based on the characteristics of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), which have prolonged incubation periods and protracted courses, exploring non-invasive physical therapy methods is essential for alleviating such diseases and ensuring that patients have an improved quality of life. Photobiomodulation (PBM) uses red and infrared light for therapeutic benefits and functions by stimulating, healing, regenerating, and protecting organizations at risk of injury, degradation, or death. Over the last two decades, PBM has gained widespread recognition as a non-invasive physical therapy method, showing efficacy in pain relief, anti-inflammatory responses, and tissue regeneration. Its application has expanded into the fields of neurology and psychiatry, where extensive research has been conducted. This paper presents a review and evaluation of studies investigating PBM in neurodegenerative diseases, with a specific emphasis on recent applications in AD and PD treatment for both animal and human subjects. Molecular mechanisms related to neuron damage and cognitive impairment are scrutinized, offering valuable insights into PBM's potential as a non-invasive therapeutic strategy. [ABSTRACT FROM AUTHOR]

ATP13A2 is a lysosomal protein involved in polyamine transport with loss of function mutations associated with multiple neurodegenerative conditions. These include early onset Parkinson's disease, Kufor-Rakeb Syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. While ATP13A2 mutations may result in clinical heterogeneity, the basal ganglia appear to be impacted in the majority of cases. The basal ganglia is particularly vulnerable to environmental exposures such as heavy metals, pesticides, and industrial agents which are also established risk factors for many neurodegenerative conditions. Not surprisingly then, impaired function of ATP13A2 has been linked to heavy metal toxicity including manganese, iron, and zinc. This review discusses the role of ATP13A2 in basal ganglia function and dysfunction, potential common pathological mechanisms in ATP13A2-related disorders, and how gene x environment interactions may contribute to basal ganglia dysfunction. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders, which affect millions worldwide, are marked by a steady decline of neurons that are selectively susceptible. Due to the complex pathological processes underlying neurodegeneration, at present, there is no viable therapy available for neurodegenerative disorders. Consequently, the establishment of a novel therapeutic approach for such conditions is a clinical void that remains. The potential significance of various peptides as neuroprotective interventions for neurodegenerative disorders is gaining increasing attention. In the past few years, there has been growing scientific interest in glucagon‐like peptide‐1 receptor agonists due to their claimed neuroprotective effects. Exendin‐4 is a glucagon‐like peptide‐1 receptor agonist that is known to possess anti‐diabetic effects and does not degrade for hours, making it a superior candidate for such disorders. Moreover, exendin‐4's neuroprotective effects have been reported in several preclinical studies. Exendin‐4's diverse therapeutic targets suggest its potential therapeutic uses in neurodegenerative ailments like Alzheimer's disease and Parkinson's disease and have garnered an increasing amount of attention. Given the substantial body of evidence supporting the neuroprotective potential of exendin‐4 in various research models, this article is dedicated to exploring the promising role of exendin‐4 as a therapeutic agent for the treatment and management of Alzheimer's disease and Parkinson's disease. This review draws insights from the findings of numerous preclinical and clinical studies to highlight the collective neuroprotective advantages of exendin‐4 and the potential mechanisms that underlie its neuroprotective effects. [ABSTRACT FROM AUTHOR]

Multiple system atrophy (MSA) is generally a sporadic neurodegenerative disease which ranks among atypical Parkinson's syndromes. The main clinical manifestation is a combination of autonomic dysfunction and parkinsonism and/or cerebellar disability. The disease may resemble other Parkinsonian syndromes, such as Parkinson's disease (PD) or progressive supranuclear palsy (PSP), from which MSA could be hardly distinguishable during the first years of progression. Due to the lack of a reliable and easily accessible biomarker, the diagnosis is still based primarily on the clinical picture. Recently, reduced levels of coenzyme Q10 (CoQ10) were described in MSA in various tissues, including the central nervous system. The aim of our study was to verify whether the level of CoQ10 in plasma and lymphocytes could serve as an easily available diagnostic biomarker of MSA. The study reported significantly lower levels of CoQ10 in the lymphocytes of patients with MSA compared to patients with PD and controls. The reduction in CoQ10 levels in lymphocytes correlated with the increasing degree of clinical involvement of patients with MSA. CoQ10 levels in lymphocytes seem to be a potential biomarker of disease progression. [ABSTRACT FROM AUTHOR]

Neuroinflammation, which is mainly triggered by microglia, is a key contributor to multiple neurodegenerative diseases. Natural products, and in particular Cannabis sativa L., due to its richness in phytochemical components, represent ideal candidates to counteract neuroinflammation. We previously characterized different C. sativa commercial varieties which showed significantly different chemical profiles. On these bases, the aim of this study was to evaluate essential oils and aqueous distillation residues from the inflorescences of three different hemp varieties for their anti-neuroinflammatory activity in BV-2 microglial cells. Cells were pretreated with aqueous residues or essential oils and then activated with LPS. Unlike essential oils, aqueous residues showed negligible effects in terms of anti-inflammatory activity. Among the essential oils, the one obtained from 'Gorilla Glue' was the most effective in inhibiting pro-inflammatory mediators and in upregulating anti-inflammatory ones through the modulation of the p38 MAPK/NF-κB pathway. Moreover, the sesquiterpenes (E)-caryophyllene, α-humulene, and caryophyllene oxide were identified as the main contributors to the essential oils' anti-inflammatory activity. To our knowledge, the anti-neuroinflammatory activity of α-humulene has not been previously described. In conclusion, our work shows that C. sativa essential oils characterized by high levels of sesquiterpenes can be promising candidates in the prevention/counteraction of neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: Multiple system atrophy with parkinsonism (MSA‐P) is a progressive condition with no effective treatment. Objective: The aim of this study was to describe the safety and efficacy of deep brain stimulation (DBS) of globus pallidus pars interna and externa in a cohort of patients with MSA‐P. Methods: Six patients were included. Changes in Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III (MDS‐UPDRS III), Parkinson's Disease Questionnaire (PDQ‐39) scores, and levodopa equivalent daily dose were compared before and after DBS. Electrode localization and volume tissue activation were calculated. Results: DBS surgery did not result in any major adverse events or intraoperative complications. Overall, no differences in MDS‐UPDRS III scores were demonstrated (55.2 ± 17.6 preoperatively compared with 67.3 ± 19.2 at 1 year after surgery), although transient improvement in mobility and dyskinesia was reported in some subjects. Conclusions: Globus pallidus pars interna and externa DBS for patients with MSA‐P did not result in major complications, although it did not provide significant clinical benefit as measured by MDS‐UPDRS III. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Parkinsonian disorders, including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) are often misdiagnosed due to overlapping symptoms and the absence of precise biomarkers. Furthermore, there are no current methods to ascertain the progression and conversion of prodromal conditions such as REM behaviour disorder (RBD). Extracellular vesicles (EVs), containing a mixture of biomolecules, have emerged as potential sources for parkinsonian diagnostics. However, inconsistencies in previous studies have left their diagnostic potential unclear. We conducted a meta-analysis, following PRISMA guidelines, to assess the diagnostic accuracy of general EVs isolated from various bodily fluids, including cerebrospinal fluid (CSF), plasma, serum, urine or saliva, in differentiating patients with parkinsonian disorders fromhealthy controls (HCs). Themeta-analysis included 21 studies encompassing 1285 patients with PD, 24 with MSA, 105 with DLB, 99 with PSP, 101 with RBD and 783 HCs. Further analyses were conducted only for patients with PD versus HCs, given the limited number for other comparisons. Using bivariate and hierarchal receiver operating characteristics (HSROC) models, the meta-analysis revealed moderate diagnostic accuracy in distinguishing patients with PD from HCs, with substantial heterogeneity and publication bias. The trim-and-fill method revealed at least two missing studies with null or low diagnostic accuracy. CSF-EVs showed better overall diagnostic accuracy, while plasma-EVs had the lowest performance. General EVs demonstrated higher diagnostic accuracy compared to CNS-originating EVs, which are more time-consuming, labour- and cost-intensive to isolate. In conclusion, while holding promise, utilizing biomarkers in general EVs for PD diagnosis remains unfeasible due to existing challenges. The focus should shift toward harmonizing the field through standardization, collaboration, and rigorous validation. Current efforts by the International Society For Extracellular Vesicles (ISEV) aim to enhance the accuracy and reproducibility of EVrelated research through rigor and standardization, aiming to bridge the gap between theory and practical clinical application. [ABSTRACT FROM AUTHOR]

Copyright of Shandong Medical Journal is the property of Shandong Medical Health Newspapers and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Parkinson's disease (PD) is a complex syndrome with many elements, such as chronic inflammation, oxidative stress, mitochondrial dysfunction, loss of dopaminergic neurons, build-up of alpha-synuclein (α-syn) in cells, and energy depletion in neurons, that drive the disease. We and others have shown that treatment with mimetics of the growth factor glucagon-like peptide 1 (GLP-1) can normalize energy utilization, neuronal survival, and dopamine levels and reduce inflammation. Liraglutide is a GLP-1 analogue that recently showed protective effects in phase 2 clinical trials in PD patients and in Alzheimer disease patients. We have developed a novel dual GLP-1/GIP receptor agonist that can cross the blood-brain barrier and showed good protective effects in animal models of PD. Here, we test liraglutide against the dual GLP-1/GIP agonist DA5-CH (KP405) in the A53T tg mouse model of PD which expresses a human-mutated gene of α-synuclein. Drug treatment reduced impairments in three different motor tests, reduced levels of α-syn in the substantia nigra, reduced the inflammation response and proinflammatory cytokine levels in the substantia nigra and striatum, and normalized biomarker levels of autophagy and mitochondrial activities in A53T mice. DA5-CH was superior in almost all parameters measured and therefore may be a better drug treatment for PD than liraglutide. [ABSTRACT FROM AUTHOR]

Introduction: The retina is the "window" of the central nervous system. Previous studies discovered that retinal thickness degenerates through the pathological process of the Alzheimer's disease (AD) continuum. Hippocampal atrophy is one of the typical clinical features and diagnostic criteria of AD. Former studies have described retinal thinning in normal aging subjects and AD patients, yet the association between retinal thickness and hippocampal atrophy in AD is unclear. The optical coherence tomography (OCT) technique has access the non-invasive to retinal images and magnetic resonance imaging can outline the volume of the hippocampus. Thus, we aim to quantify the correlation between these two parameters to identify whether the retina can be a new biomarker for early AD detection. Methods: We systematically searched the PubMed, Embase, and Web of Science databases from inception to May 2023 for studies investigating the correlation between retinal thickness and hippocampal volume. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the study quality. Pooled correlation coefficient r values were combined after Fisher's Z transformation. Moderator effects were detected through subgroup analysis and the meta-regression method. Results: Of the 1,596 citations initially identified, we excluded 1,062 studies after screening the titles and abstract (animal models, n = 99; irrelevant literature, n = 963). Twelve studies met the inclusion criteria, among which three studies were excluded due to unextractable data. Nine studies were eligible for this meta-analysis. A positive moderate correlation between the retinal thickness was discovered in all participants of with AD, mild cognitive impairment (MCI), and normal controls (NC) (r = 0.3469, 95% CI: 0.2490-0.4377, I² = 5.0%), which was significantly higher than that of the AD group (r = 0.1209, 95% CI:0.0905- 0.1510, I² = 0.0%) (p < 0.05). Among different layers, the peripapillary retinal nerve fiber layer (pRNFL) indicated a moderate positive correlation with hippocampal volume (r = 0.1209, 95% CI:0.0905-0.1510, I² = 0.0%). The retinal pigmented epithelium (RPE) was also positively correlated [r = 0.1421, 95% CI:(-0.0447-0.3192), I² = 84.1%]. The retinal layers and participants were the main overall heterogeneity sources. Correlation in the bilateral hemisphere did not show a significant difference. Conclusion: The correlation between RNFL thickness and hippocampal volume is more predominant in both NC and AD groups than other layers. Whole retinal thickness is positively correlated to hippocampal volume not only in AD continuum, especially in MCI, but also in NC. [ABSTRACT FROM AUTHOR]

Differentiated status, low regenerative capacity and complex signaling make neuronal tissues highly susceptible to translating an imbalance in cell homeostasis into cell death. The high rate of neurodegenerative diseases in the elderly population confirms this. The multiple and divergent signaling cascades downstream of the various stress triggers challenge researchers to identify the central components of the stress-induced signaling pathways that cause neurodegeneration. Because of their critical role in cell homeostasis, kinases have emerged as one of the key regulators. Among kinases, non-receptor tyrosine kinase (Abelson kinase) c-Abl appears to be involved in both the normal development of neural tissue and the development of neurodegenerative pathologies when abnormally expressed or activated. However, exactly how c-Abl mediates the progression of neurodegeneration remains largely unexplored. Here, we summarize recent findings on the involvement of c-Abl in normal and abnormal processes in nervous tissue, focusing on neurons, astrocytes and microglial cells, with particular reference to molecular events at the interface between stress signaling, DNA damage, and metabolic regulation. Because inhibition of c-Abl has neuroprotective effects and can prevent neuronal death, we believe that an integrated view of c-Abl signaling in neurodegeneration could lead to significantly improved treatment of the disease. [ABSTRACT FROM AUTHOR]

Copyright of Der Nervenarzt is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We describe an unusual presentation of myeloperoxidase positive antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis managed by a multidisciplinary approach. A 75-year-old man gave a 3-week history of proximal lower limb weakness and exertional myalgia. His serum creatine kinase was normal and many of his non-specific symptoms suggested small vessel vasculitis. His investigations for common causes of muscle weakness were normal, and renal biopsy was normal despite haemoproteinuria. CT scan of the chest identified a pulmonary nodule of uncertain significance, not amenable to biopsy. MR scan of the thighs showed muscle oedema, and muscle biopsy confirmed typical features of vasculitis. Following high-dose corticosteroids his exertional myalgia quickly resolved and his normal mobility returned. Early immunosuppression is essential to improving clinical outcomes in ANCA-associated vasculitis, but diagnostic investigations often lack sensitivity. [ABSTRACT FROM AUTHOR]

Introduction: The term vasculitis refers to a heterogeneous group of diseases, all characterized by inflammation and destruction of blood vessel walls leading to ischemic, thrombotic, and hemorrhagic damage to tissues of central and peripheral nervous system. The main indication for triple biopsy (skin, muscle and nerve) is to rule out peripheral vasculitis neuropathy. However, the drawback is that any systemic inflammatory process may show changes in a skin biopsy and hence these changes need to be interpreted with caution. The aim of this study is to establish the diagnostic yield and the usefulness of the triple biopsies in clinically suspected cases of vasculitis. Material and Methods: The present study was conducted in the Department of General Pathology, SBKS MI & RC, Vadodara over a period of one year (1/1/2022 to 31/12/2022). All the clinically suspected cases of vasculitis received at OPD were included in the study. Any case with either muscle, nerve or skin biopsy reported as inadequate were excluded from the study. Results: On evaluation the usefulness of triple biopsies for vasculitis, we found a very low diagnostic yield with only 3.3% of peripheral nerve biopsy and 0.8% of muscle and nerve biopsy showed definite vasculitis. In case of suspected peripheral/systemic vasculitic neuropathy, nerve biopsy was sufficient in the majority of case and has the diagnostic armamentarium for the evaluation of vasculitis. Conclusion: In conclusion, nerve biopsies provide the best yield for the diagnosis of vasculitis, as opposed to muscle and skin biopsies. The role of triple biopsies as a routine protocol for the evaluation of vasculitis is questionable. [ABSTRACT FROM AUTHOR]

Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have been linked to lysosomal de-acidification through impairing the vacuolar-type ATPase and ion channels on the organelle membrane. Similar lysosomal abnormalities are also present in sporadic forms of neurodegeneration, although the underlying pathogenic mechanisms are unclear and remain to be investigated. Importantly, recent studies have revealed early occurrence of lysosomal acidification impairment before the onset of neurodegeneration and late-stage pathology. However, there is a lack of methods for organelle pH monitoring in vivo and a dearth of lysosome-acidifying therapeutic agents. Here, we summarize and present evidence for the notion of defective lysosomal acidification as an early indicator of neurodegeneration and urge the critical need for technological advancement in developing tools for lysosomal pH monitoring and detection both in vivo and for clinical applications. We further discuss current preclinical pharmacological agents that modulate lysosomal acidification, including small molecules and nanomedicine, and their potential clinical translation into lysosome-targeting therapies. Both timely detection of lysosomal dysfunction and development of therapeutics that restore lysosomal function represent paradigm shifts in targeting neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Parkinson's Disease (PD) remains a significant focus of extensive research aimed at developing effective therapeutic strategies. Current treatments primarily target symptom management, with limited success in altering the course of the disease. This shortfall underscores the urgent need for novel therapeutic approaches that can modify the progression of PD.This review concentrates on emerging therapeutic targets poised to address the underlying mechanisms of PD. Highlighted novel and emerging targets include Protein Abelson, Rabphilin-3 A, Colony Stimulating Factor 1-Receptor, and Apelin, each showing promising potential in preclinical and clinical settings for their ability to modulate disease progression. By examining recent advancements and outcomes from trials focusing on these targets, the review aims to elucidate their efficacy and potential as disease-modifying therapies.Furthermore, the review explores the concept of multi-target approaches, emphasizing their relevance in tackling the complex pathology of PD. By providing comprehensive insights into these novel targets and their therapeutic implications, this review aims to guide future research directions and clinical developments toward more effective treatments for PD and related neurodegenerative disorders., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mutations in ATP13A2 (PARK9), an autophagy-related protein, cause Kufor–Rakeb syndrome, an autosomal recessive, juvenile-onset form of parkinsonism. α-Synuclein (α-syn) is a presynaptic neuronal protein that forms toxic aggregates in Parkinson's disease (PD). We studied α-syn aggregation and autophagic flux in ATP13A2-knockdown Drosophila expressing either wild-type (WT) or mutant α-syn. Dopaminergic (DA) neuron loss was studied by confocal microscopy. Sleep and circadian activity were evaluated in young and old flies using a Drosophila activity monitor. Thirty-day-old ATP13A2-RNAi A53T-α-syn flies had increased Triton-insoluble α-syn levels, compared to control A53T-α-syn flies without ATP13A2-RNAi. Whole-brain staining revealed significantly fewer dopaminergic (DA) neurons in the PPL2 cluster of 30-day-old ATP13A2-RNAi flies expressing WT-, A30P-, and A53T-α-syn than in that of controls. In ATP13A2-RNAi A53T-α-syn flies, autophagic flux was decreased, as indicated by increased accumulation of Ref(2)P, the Drosophila p62 homologue. ATP13A2 silencing decreased total locomotor activity in young, and enhanced sleep features, similar to PD (decreasing bout length), in old flies expressing A53T-α-syn. ATP13A2 silencing also altered the circadian locomotor activity of A30P- and A53T-α-syn flies. Thus, ATP13A2 may play a role in the autophagic degradation of A53T-α-syn. [ABSTRACT FROM AUTHOR]

Besides motor symptoms, many individuals with Parkinson's disease develop cognitive impairment perhaps due to coexisting α-synuclein and Alzheimer's disease pathologies and impaired brain insulin signalling. Discovering biomarkers for cognitive impairment in Parkinson's disease could help clarify the underlying pathogenic processes and improve Parkinson's disease diagnosis and prognosis. This study used plasma samples from 273 participants: 103 Parkinson's disease individuals with normal cognition, 121 Parkinson's disease individuals with cognitive impairment (81 with mild cognitive impairment, 40 with dementia) and 49 age- and sex-matched controls. Plasma extracellular vesicles enriched for neuronal origin were immunocaptured by targeting the L1 cell adhesion molecule, then biomarkers were quantified using immunoassays. α-Synuclein was lower in Parkinson's disease compared to control individuals (P = 0.004) and in cognitively impaired Parkinson's disease individuals compared to Parkinson's disease with normal cognition (P < 0.001) and control (P < 0.001) individuals. Amyloid-β42 did not differ between groups. Phosphorylated tau (T181) was higher in Parkinson's disease than control individuals (P = 0.003) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and controls (P < 0.001). Total tau was not different between groups. Tyrosine-phosphorylated insulin receptor substrate-1 was lower in Parkinson's disease compared to control individuals (P = 0.03) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and controls (P = 0.01), and also decreased with increasing motor symptom severity (P = 0.005); serine312-phosphorylated insulin receptor substrate-1 was not different between groups. Mechanistic target of rapamycin was not different between groups, whereas phosphorylated mechanistic target of rapamycin trended lower in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.05). The ratio of α-synuclein to phosphorylated tau181 was lower in Parkinson's disease compared to controls (P = 0.001), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and decreased with increasing motor symptom severity (P < 0.001). The ratio of insulin receptor substrate-1 phosphorylated serine312 to insulin receptor substrate-1 phosphorylated tyrosine was higher in Parkinson's disease compared to control individuals (P = 0.01), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and increased with increasing motor symptom severity (P = 0.003). α-Synuclein, phosphorylated tau181 and insulin receptor substrate-1 phosphorylated tyrosine contributed in diagnostic classification between groups. These findings suggest that both α-synuclein and tau pathologies and impaired insulin signalling underlie Parkinson's disease with cognitive impairment. Plasma neuronal extracellular vesicles biomarkers may inform cognitive prognosis in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Current therapeutics targeting chronic phases of multiple sclerosis (MS) are considerably limited in reversing the neural damage resulting from repeated inflammation and demyelination insults in the multi-focal lesions. This inflammation is propagated by the activation of microglia, the endogenous immune cell aiding in the central nervous system homeostasis. Activated microglia may transition into polarized phenotypes; namely, the classically activated proinflammatory phenotype (previously categorized as M1) and the alternatively activated anti-inflammatory phenotype (previously, M2). These transitional microglial phenotypes are dynamic states, existing as a continuum. Shifting microglial polarization to an anti-inflammatory status may be a potential therapeutic strategy that can be harnessed to limit neuroinflammation and further neurodegeneration in MS. Our research has observed that the obstruction of signaling by inhibitory myelin proteins such as myelin-associated inhibitory factor, Nogo-A, with its receptor (NgR), can regulate microglial cell function and activity in pre-clinical animal studies. Our review explores the microglial role and polarization in MS pathology. Additionally, the potential therapeutics of targeting Nogo-A/NgR cellular mechanisms on microglia migration, polarization and phagocytosis for neurorepair in MS and other demyelination diseases will be discussed. [ABSTRACT FROM AUTHOR]

Age‐related macular degeneration (AMD) is a leading cause of blindness. Vision loss is caused by the retinal pigment epithelium (RPE) and photoreceptors atrophy and/or retinal and choroidal angiogenesis. Here we use AMD patient‐specific RPE cells with the Complement Factor H Y402H high‐risk polymorphism to perform a comprehensive analysis of extracellular vesicles (EVs), their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced polarised EV secretion. Multi‐omics analyses demonstrate that AMD RPE EVs carry RNA, proteins and lipids, which mediate key AMD features including oxidative stress, cytoskeletal dysfunction, angiogenesis and drusen accumulation. Moreover, AMD RPE EVs induce amyloid fibril formation, revealing their role in drusen formation. We demonstrate that exposure of control RPE to AMD RPE apical EVs leads to the acquisition of AMD features such as stress vacuoles, cytoskeletal destabilization and abnormalities in the morphology of the nucleus. Retinal organoid treatment with apical AMD RPE EVs leads to disrupted neuroepithelium and the appearance of cytoprotective alpha B crystallin immunopositive cells, with some co‐expressing retinal progenitor cell markers Pax6/Vsx2, suggesting injury‐induced regenerative pathways activation. These findings indicate that AMD RPE EVs are potent inducers of AMD phenotype in the neighbouring RPE and retinal cells. [ABSTRACT FROM AUTHOR]

Insulin desensitization has been observed in the brains of patients with Parkinson's disease (PD), which is a progressive neurodegenerative disorder for which there is no cure. Semaglutide is a novel long-actingglucagon-likepeptide-1 (GLP-1) receptor agonist that is on the market as a treatment for type 2 diabetes. It is in a phase II clinical trial in patients with PD. Two previous phase II trials in PD patients showed good effects with the older GLP-1 receptor agonists, exendin-4 and liraglutide. We have developed a dual GLP-1/GIP receptor agonist (DA5-CH) that can cross the blood-brain barrier (BBB) at a higher rate than semaglutide. We tested semaglutide and DA5-CH in the 6-OHDA-lesion rat model of PD. Treatment was semaglutide or DA5-CH (25 nmol/kg, i.p.) daily for 30 days postlesion. Both drugs reduced the apomorphine-induced rotational behavior and alleviated dopamine depletion and the inflammation response in the lesioned striatum as shown in reduced IL-1β and TNF-α levels, with DA5-CH being more effective. In addition, both drugs protected dopaminergic neurons and increased TH expression in the substantia nigra. Furthermore, the level of monomer and aggregated α-synuclein was reduced by the drugs, and insulin resistance as shown in reduced pIRS-1ser312 phosphorylation was also attenuated after drug treatment, with DA5-CH being more effective. Therefore, while semaglutide showed good effects in this PD model, DA5-CH was superior and may be a better therapeutic drug for neurodegenerative disorders such as PD than GLP-1 receptor agonists that do not easily cross the BBB. [ABSTRACT FROM AUTHOR]

Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson's disease dementia) apart from cholinesterase inhibitors. We reviewed several promising compounds that might potentially be disease-modifying agents for Lewy body dementia and then undertook an International Delphi consensus study to prioritise compounds. We identified ambroxol as the top ranked agent for repurposing and identified a further six agents from the classes of tyrosine kinase inhibitors, GLP-1 receptor agonists, and angiotensin receptor blockers that were rated by the majority of our expert panel as justifying a clinical trial. It would now be timely to take forward all these compounds to Phase II or III clinical trials in Lewy body dementia. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum-mitochondria contact sites regulate various biological processes, such as mitochondrial dynamics, calcium homeostasis, autophagy and lipid metabolism. Notably, dysfunctions in these contact sites are closely related to neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. However, details about the role of endoplasmic reticulum-mitochondria contact sites in neurodegenerative diseases remain unknown. In Parkinson's disease, interactions between α-synuclein in the contact sites and components of tether complexes that connect organelles can lead to various dysfunctions, especially with regards to calcium homeostasis. This review will summarize the main tether complexes present in endoplasmic reticulum-mitochondria contact sites, and their roles in calcium homeostasis and trafficking. We will discuss the impact of α-synuclein accumulation, its interaction with tethering complex components and the implications in Parkinson's disease pathology. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2DM) is an established risk factor for developing Parkinson's disease (PD), but its effect on disease progression is not well understood. Objective: The aim of this study was to investigate the influence of T2DM on aspects of disease progression in PD. Methods: We analyzed data from the Tracking Parkinson's study to examine the effects of comorbid T2DM on PD progression and quality of life by comparing symptom severity scores assessing a range of motor and nonmotor symptoms. Results: We identified 167 (8.7%) patients with PD and T2DM (PD + T2DM) and 1763 (91.3%) patients with PD without T2DM (PD). After controlling for confounders, patients with T2DM had more severe motor symptoms, as assessed by Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (25.8 [0.9] vs. 22.5 [0.3] P = 0.002), and nonmotor symptoms, as assessed by Non‐Motor Symptoms Scale total (38.4 [2.5] vs. 31.8 [0.7] P < 0.001), and were significantly more likely to report loss of independence (odds ratio, 2.08; 95% confidence interval [CI]: 1.34–3.25; P = 0.001) and depression (odds ratio, 1.62; CI: 1.10–2.39; P = 0.015). Furthermore, over time, patients with T2DM had significantly faster motor symptom progression (P = 0.012), developed worse mood symptoms (P = 0.041), and were more likely to develop substantial gait impairment (hazard ratio, 1.55; CI: 1.07–2.23; P = 0.020) and mild cognitive impairment (hazard ratio, 1.7; CI: 1.24–2.51; P = 0.002) compared with the PD group. Conclusions: In the largest study to date, T2DM is associated with faster disease progression in Parkinson's, highlighting an interaction between these two diseases. Because it is a potentially modifiable metabolic state, with multiple peripheral and central targets for intervention, it may represent a target for alleviating parkinsonian symptoms and slowing progression to disability and dementia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterized by cell loss in the substantia nigra and the presence of alpha-synuclein (α-syn)-containing neuronal Lewy bodies. While α-syn has received major interest in the pathogenesis of PD, the function of beta- and gamma-synucleins (β-syn and γ-syn, respectively) is not really known. Yet, these proteins are members of the same family and also concentrated in neuronal terminals. The current preclinical study investigated the expression levels of α-, β-, and γ-synucleins in brainstem regions involved in PD physiopathology. We analyzed synuclein expression in the substantia nigra, raphe nuclei, pedunculopontine nucleus, and locus coeruleus from control and parkinsonian (by MPTP) macaques. MPTP-intoxicated monkeys developed a more or less severe parkinsonian score and were sacrificed after a variable post-MPTP period ranging from 1 to 20 months. The expression of the three synucleins was increased in the substantia nigra after MPTP, and this increase correlates positively, although not very strongly, with cell loss and motor score and not with the time elapsed after intoxication. In the dorsal raphe nucleus, the expression of the three synucleins was also increased, but only α- and γ-Syn are linked to the motor score and associated cell loss. Finally, although no change in synuclein expression was demonstrated in the locus coeruleus after MPTP, we found increased expression levels of γ-Syn, which are only correlated with cell loss in the pedunculopontine nucleus. Altogether, our data suggest that these proteins may play a key role in brainstem regions and mesencephalic tegmentum. Given the involvement of these brain regions in non-motor symptoms of PD, these data also strengthen the relevance of the MPTP macaque model of PD, which exhibits pathological changes beyond nigral DA cell loss and α-synucleinopathy. [ABSTRACT FROM AUTHOR]

Most neurodegenerative diseases such as Alzheimer's disease are proteinopathies linked to the toxicity of amyloid oligomers. Treatments to delay or cure these diseases are lacking. Using budding yeast, we report that the natural lipid tripentadecanoin induces expression of the nitric oxide oxidoreductase Yhb1 to prevent the formation of protein aggregates during aging and extends replicative lifespan. In mammals, tripentadecanoin induces expression of the Yhb1 orthologue, neuroglobin, to protect neurons against amyloid toxicity. Tripentadecanoin also rescues photoreceptors in a mouse model of retinal degeneration and retinal ganglion cells in a Rhesus monkey model of optic atrophy. Together, we propose that tripentadecanoin affects p‐bodies to induce neuroglobin expression and offers a potential treatment for proteinopathies and retinal neurodegeneration. [ABSTRACT FROM AUTHOR]

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

Glutamate neurotransmission and metabolism are finely modulated by the retinal network, where the efficient processing of visual information is shaped by the differential distribution and composition of glutamate receptors and transporters. However, disturbances in glutamate homeostasis can result in glutamate excitotoxicity, a major initiating factor of common neurodegenerative diseases. Within the retina, glutamate excitotoxicity can impair visual transmission by initiating degeneration of neuronal populations, including retinal ganglion cells (RGCs). The vulnerability of RGCs is observed not just as a result of retinal diseases but has also been ascribed to other common neurodegenerative and peripheral diseases. In this review, we describe the vulnerability of RGCs to glutamate excitotoxicity and the contribution of different glutamate receptors and transporters to this. In particular, we focus on the N-methyl-d-aspartate (NMDA) receptor as the major effector of glutamate-induced mechanisms of neurodegeneration, including impairment of calcium homeostasis, changes in gene expression and signalling, and mitochondrial dysfunction, as well as the role of endoplasmic reticular stress. Due to recent developments in the search for modulators of NMDA receptor signalling, novel neuroprotective strategies may be on the horizon. [ABSTRACT FROM AUTHOR]

Objective: To explore the roles of striatal subdivisions in the pathogenesis of frontotemporal dementia with parkinsonism (FTDP) in a patient resulting from prion protein gene (PRNP) mutation. Methods: This patient received clinical interviews and underwent neuropsychological assessments, genetic testing, [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET)/MRI, and [18F]-dihydrotetrabenazine positron emission tomography ([18F]-DTBZ PET)/CT. Region-of-interest analysis was conducted concerning metabolism, and dopamine transport function between this patient and 12 controls, focusing on the striatum subregions according to the Oxford-GSK-Imanova Striatal Connectivity Atlas. Results: A 64-year-old man initially presented with symptoms of motor dysfunction and subsequently behavioral and personality changes. FTDP was initially suspected. Sequence analysis disclosed a valine to isoleucine at codon 180 in PRNP. Compared to controls, this patient had a severe reduction (> 2SD) of standard uptake value ratio (SUVR) in the limbic and executive subregions but relative retention of metabolism in rostral motor and caudal motor subregions using [18F]-FDG PET/MRI, and the SUVR decreased significantly across the striatal in [18F]-DTBZ PET/CT, especially in the rostral motor and caudal motor subregions. Conclusion: The alteration of frontal striatal loops may be involved in cognitive impairment in FTDP, and the development of parkinsonism in FTDP may be primarily due to the involvement of the presynaptic nigrostriatal loops in PRNP V180I mutation. [ABSTRACT FROM AUTHOR]

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

Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria (MIT) in muscle could trigger inflammation in the context of aging is still unknown. Here, we demonstrate that BCL2 interacting protein 3 (BNIP3) plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of Toll‐like receptor 9 (TLR9)‐dependent inflammation and activation of the NLRP3 (nucleotide‐binding oligomerization domain (NOD)‐, leucine‐rich repeat (LRR)‐, and pyrin domain‐containing protein 3) inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age‐induced muscle inflammation in mice and humans. Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging. [ABSTRACT FROM AUTHOR]