LRRK2-G2019S is the most common pathogenic LRRK2 mutation which accounts for up to 13% of cases of familial Parkinson’s disease. The LRRK2-G2019S mutation has incomplete penetrance which increases with age. Molecular mechanisms which contribute to the disease status in LRRK2-G2019S mutation carriers are yet to be fully defined. Here, we aimed to further investigate the specific mitochondrial effects of LRRK2-G2019S penetrance in a cohort of patient-derived fibroblasts from manifesting and non-manifesting LRRK2-G2019S carriers compared to controls to further elucidate the pathogenic mechanism of the mutation. We find a significant reduction of 50% in the expression of the complex IV assembly factor SCO2 in LRRK2-G2019S manifesting fibroblasts. In contrast, SCO2 levels remained similar to controls in non-manifesting LRRK2-G2019S carriers. A small reduction in complex IV subunit expression accompanied this reduction in SCO2 in manifesting LRRK2-G2019S carriers. Despite the role of SCO2 in copper incorporation into complex IV, we identified no differences in the unbound mitochondrial copper content in a limited number of manifesting or non-manifesting LRRK2-G2019S carriers compared to controls. However, LRRK2-G2019S carriers exhibit variable cellular phenotypes in mitochondrial morphology, mitochondrial membrane potential and cellular ATP or ROS production which does not differ significantly between manifesting and non-manifesting carriers. We conclude that mitochondrial complex IV deficiency could be a pathogenic mechanism of the LRRK2-G2019S mutation which may be attributed to a reduction in SCO2, however there is evident heterogeneity in the cellular phenotype of LRRK2-G2019S carriers which may suggest underlying compensatory mechanisms.

Abstract Mitochondrial dysfunction is implicated in a variety of complex neurological disorders. Primary mitochondrial diseases are caused directly by mutations in genes encoding mitochondrial proteins, leading to mitochondrial dysfunction and disease. Mitochondrial dysfunction is also a key contributor to pathogenesis in multiple neurodegenerative diseases. Rescue of mitochondrial function is therefore an attractive therapeutic target in both groups of diseases. In this study, we used primary fibroblasts derived from patients with the primary mitochondrial disease Leigh syndrome (LS) and the neurodegenerative disease Huntington’s disease (HD) to investigate mitochondrial phenotypes in these patients. We used these to identify modifiable measures of mitochondrial phenotype using a high content imaging screen. Despite having distinct underlying disease causes, different mitochondrial phenotypes in LS and HD patient derived cells converged on an imbalance between functional and dysfunctional mitochondria. Through multi-parameter screening of the mitochondrial phenotype we identified the AMPK activator A769662 as a small molecule able to rescue this imbalance in both LS and HD patient derived fibroblasts via different pathways. Our findings indicate that high throughput screening for mitochondrial phenotypes could identify novel therapeutic agents to rescue mitochondrial dysfunction in complex neurological disorders. Research in Context Evidence before this study Mitochondrial dysfunction is the primary driver of mitochondrial disease and key contributing factor to neurodegenerative disease pathogenesis. Rescuing mitochondrial function is a promising therapeutic strategy, yet strategies to identify mitochondrial modulators in patient cells are limited. Added value of this study Our in-depth mitochondrial characterisation of Leigh syndrome and Huntington’s disease patient fibroblasts shows the potential for using this methodology to identify mitochondrial therapeutics. We identify a mitochondrial phenotype common across diseases and an AMPK activator capable of rescuing this phenotype. Implications of all the available evidence Our work extends our understanding of the mitochondrial dysfunction associated with Leigh syndrome and Huntington’s disease and expands the tool set available for identifying modulators of mitochondrial health as potential therapeutics for complex neurological disorders.

Single nucleotide polymorphisms adjacent to the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) gene have been associated with Parkinson’s disease (PD) in genome-wide association studies (GWAS). However, its biological validation as a PD risk gene has been hampered by the lack of available models. Using CRISPR/Cas9, we generated a zebrafish model of acmsd deficiency with marked increase in quinolinic acid. Despite this, acmsd-/- zebrafish were viable, fertile, morphologically normal and demonstrated no abnormalities in spontaneous movement. In contrast to the postulated pro-immune pathomechanism linking ACMSD to PD, microglial cells and expression of the proinflammatory cytokines cxcl8, il-1β, and mmp9 were similar between acmsd-/- and controls. The number of ascending dopaminergic neurons, and their susceptibility to MPP+, was also indistinguishable. An upregulation of kynurenine aminotransferase activity was identified in acmsd-/- zebrafish which may explain the absence of neurodegenerative phenotypes. Our study highlights the importance of biological validation for putative GWAS hits in suitable model systems.

BACKGROUND:There are currently no disease-modifying therapies (DMTs) registered for Parkinson's disease (PD). The Edmond J. Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative will expedite clinical assessment of putative DMTs through a multi-arm multistage (MAMS) trial, testing several treatments against a common placebo arm and replacing unsuccessful therapies early. OBJECTIVE:The objective of this study was to describe the treatment selection process for the EJS ACT-PD clinical trial platform. METHODS:A Treatment Selection Working Group (TSWG) identified compounds using complementary strategies, such as literature search, related initiatives (Cure Parkinson's International Linked Clinical Trials [iLCT] initiative), and expert suggestions. Compounds were classified into five mechanistic subgroups (mitochondrial, lysosomal, protein, inflammation, "other"). "Go/No-Go" criteria and a scoring system covering preclinical, pharmacological, and clinical evidence were devised. Experts scored the candidates for quantitative rankings. Dossiers adapted from iLCT documents were produced for the top-ranked compounds and in turn prioritized by the TSWG. Practical and logistical considerations from the Steering Committee (SC) guided the final decision. Patient and Public Involvement and Engagement representatives provided feedback throughout the process. RESULTS:A total of 293 interventions were identified, 52 of which passed the "Go/No-Go" criteria and were scored. Dossiers of the 14 top-ranked compounds were submitted to the SC. Telmisartan, terazosin, and ursodeoxycholic acid were selected as the initial interventions. CONCLUSIONS:Drug selection in DMT PD MAMS trials requires consideration of scientific and practical issues. We present a robust system that can inform similar initiatives. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The seeding of α-Synuclein (αSyn) is a key driver of Lewy pathology propagation in Parkinson’s disease (PD) and forms the basis for recent diagnostic advances. However, it remains unclear how the structural and biochemical features of αSyn seeds dictate their propagation efficiency, capacity to induce Lewy body formation, and resulting cellular toxicity. Using genetic and idiopathic PD cell models, we map the pathogenic cascade beginning with the seed-driven conversion of endogenous αSyn, followed by impaired degradation, mitochondrial dysfunction, and ultimately Lewy body formation. By coupling kinetic modelling of aggregation with functional readouts, we identify secondary nucleation as the predominant mechanism generating toxic αSyn aggregation intermediates, identifying the critical process that links seeding to pathology. Extending this framework to PD brain, we quantitatively correlate seeding capacity with the spatiotemporal spread and severity of Lewy pathology, revealing a mechanistic connection between αSyn aggregation dynamics and disease progression at molecular, cellular, and anatomical levels. By unifying molecular mechanism with clinicopathological progression, our work identifies catalytic αSyn fibrillar seeds as tractable targets for both disease-modifying therapy and biomarker development in PD. αSyn fibril-oligomer interplay drives mitochondrial abnormalities and Lewy pathology Fibrillar αSyn catalyse toxic aggregate formations via secondary nucleation Phosphorylated αSyn evades lysosomal clearance and drives enhanced dysfunctions Seeding capacity of αSyn predicts Lewy pathology burden and disease progression

Parkinson disease (PD) is a progressive neurodegenerative condition characterised by tremor, bradykinesia and rigidity, as well as other motor and non-motor symptoms, for which no effective disease-modifying treatments have been discovered. Neuroprotection in PD is limited by its clinical and biological heterogeneity, suboptimal preclinical models, lack of established disease progression biomarkers, complex pathophysiology, the existence of effective symptomatic therapies which hamper the detection of actual disease modification, and trial design. This review discusses the above issues and other important concepts in neuroprotection in PD. The main pathophysiological mechanisms in PD are classified into mitochondrial dysfunction, lysosomal dysfunction, inflammation, protein aggregation/propagation, and "other", and discussed briefly. The most relevant disease-modifying candidates in PD are classified into the aforementioned categories and reviewed. Finally, conclusions and recommendations for future improvements in the field of disease modification in PD are provided.

INTRODUCTION: The study aimed to compare cognitive trajectories between patients with reports of social isolation and loneliness and those without. METHODS: Reports of social isolation, loneliness, and Montreal Cognitive Assessment (MoCA) scores were extracted from dementia patients' medical records using Natural Language Processing models and analysed using mixed-effects models. RESULTS: Lonely patients (n = 382) showed lower MoCA scores throughout the disease (B = -0.83, t = -2.64, p = 0.008). Socially isolated patients (n = 523) experienced faster cognitive decline six months before diagnosis (B = -0.21, t = -2.18, p = 0.029), but were comparable to controls (n = 3912) before this period. This led to lower MoCA scores at diagnosis (B = -0.69, t = -2.53, p = 0.011) and in later stages. DISCUSSION: Lower cognitive levels in lonely and socially isolated patients suggest that these factors may contribute to dementia progression. KEYWORDS: Social isolation, Loneliness, Electronic Health Records, Natural Language Processing, Tertiary prevention ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by CRIS Powered by Akrivia Health, using data, systems and support from the NIHR Oxford Health Biomedical Research Centre (NIHR203316) Research Informatics Team. IK is funded through MRC, NIHR Oxford Health Biomedical Research Facility and an investigator-initiated grant by Novo Nordisk. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics Application Review Board of the University of Sheffield gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All patient data used in the present study are accessible through the UK-CRIS system. The source data for this work is owned by Oxford Health NHS Foundation Trust using anonymised patient records via CRIS Powered by Akrivia Health. The data cannot be made publicly available but can be accessed with permissions from Oxford Health NHS Foundation Trust for UK NHS staff and UK academics within a secure firewall, in the same manner as the authors. The R and Python code used to analyse the data and develop NLP models is reported in supporting materials.

INTRODUCTION:The study aimed to compare cognitive trajectories between patients with reports of social isolation and loneliness and those without. METHODS:Reports of social isolation, loneliness, and Montreal Cognitive Assessment (MoCA) scores were extracted from dementia patients' medical records using natural language processing models and analyed using mixed-effects models. RESULTS:Lonely patients (n = 382), compared to controls (n = 3912), showed an average MoCA score that was 0.83 points lower at diagnosis (P = 0.008) and throughout the disease. Socially isolated patients (n = 523) experienced a 0.21 MoCA point per year faster rate of cognitive decline in the 6 months before diagnosis (P = 0.029), but were comparable to controls before this period. This led to average MoCA scores that were 0.69 MoCA points lower at diagnosis (P = 0.011). DISCUSSION:Lower cognitive levels in lonely and socially isolated patients suggest that these factors may contribute to dementia progression. Highlights:Developed Natural Language Processing model to detect social isolation and loneliness in electronic health records.Patients with loneliness reports have lower Montreal Cognitive Assessment (MoCA) scores than other patients.Social isolation was related to the faster decline in MoCA scores before diagnosis.Social isolation and loneliness are promising targets for slowing cognitive decline.

OBJECTIVE:The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that a fraction of iPD patients may harbor a combination of common variants in nuclear-encoded mitochondrial genes ultimately resulting in neurodegeneration. METHODS:We used mitochondria-specific polygenic risk scores (mitoPRSs) and created pathway-specific mitoPRSs using genotype data from different iPD case-control datasets worldwide, including the Luxembourg Parkinson's Study (412 iPD patients and 576 healthy controls) and COURAGE-PD cohorts (7,270 iPD cases and 6,819 healthy controls). Cellular models from individuals stratified according to the most significant mitoPRS were subsequently used to characterize different aspects of mitochondrial function. RESULTS:Common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk in independent cohorts (Luxembourg Parkinson's Study odds ratio, OR = 1.31[1.14-1.50], p-value = 5.4e-04; COURAGE-PD OR = 1.23[1.18-1.27], p-value = 1.5e-29). Functional analyses in fibroblasts and induced pluripotent stem cells-derived neuronal progenitors revealed significant differences in mitochondrial respiration between iPD patients with high or low OXPHOS-PRS (p-values < 0.05). Clinically, iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients (false discovery rate [FDR]-adj p-value = 0.015), similar to prototypic monogenic forms of PD. Finally, iPD patients with high OXPHOS-PRS responded more effectively to treatment with mitochondrially active ursodeoxycholic acid. INTERPRETATION:OXPHOS-PRS may provide a precision medicine tool to stratify iPD patients into a pathogenic subgroup genetically defined by specific mitochondrial impairment, making these individuals eligible for future intelligent clinical trial designs. ANN NEUROL 2024;96:133-149.

The heterogenous aetiology of Parkinson's disease is increasingly recognized; both mitochondrial and lysosomal dysfunction have been implicated. Powerful, clinically applicable tools are required to enable mechanistic stratification for future precision medicine approaches. The aim of this study was to characterize bioenergetic dysfunction in Parkinson's disease by applying a multimodal approach, combining standardized clinical assessment with midbrain and putaminal 31-phosphorus magnetic resonance spectroscopy (31P-MRS) and deep phenotyping of mitochondrial and lysosomal function in peripheral tissue in patients with recent-onset Parkinson's disease and control subjects. Sixty participants (35 patients with Parkinson's disease and 25 healthy controls) underwent 31P-MRS for quantification of energy-rich metabolites [ATP, inorganic phosphate (Pi) and phosphocreatine] in putamen and midbrain. In parallel, skin biopsies were obtained from all research participants to establish fibroblast cell lines for subsequent quantification of total intracellular ATP and mitochondrial membrane potential (MMP) as well as mitochondrial and lysosomal morphology, using high content live cell imaging. Lower MMP correlated with higher intracellular ATP (r = -0.55, P = 0.0016), higher mitochondrial counts (r = -0.72, P < 0.0001) and higher lysosomal counts (r = -0.62, P = 0.0002) in Parkinson's disease patient-derived fibroblasts only, consistent with impaired mitophagy and mitochondrial uncoupling. 31P-MRS-derived posterior putaminal Pi/ATP ratio variance was considerably greater in Parkinson's disease than in healthy controls (F-tests, P = 0.0036). Furthermore, elevated 31P-MRS-derived putaminal, but not midbrain Pi/ATP ratios (indicative of impaired oxidative phosphorylation) correlated with both greater mitochondrial (r = 0.37, P = 0.0319) and lysosomal counts (r = 0.48, P = 0.0044) as well as lower MMP in both short (r = -0.52, P = 0.0016) and long (r = -0.47, P = 0.0052) mitochondria in Parkinson's disease. Higher 31P-MRS midbrain phosphocreatine correlated with greater risk of rapid disease progression (r = 0.47, P = 0.0384). Our data suggest that impaired oxidative phosphorylation in the striatal dopaminergic nerve terminals exceeds mitochondrial dysfunction in the midbrain of patients with early Parkinson's disease. Our data further support the hypothesis of a prominent link between impaired mitophagy and impaired striatal energy homeostasis as a key event in early Parkinson's disease.

Innovative approaches to conducting proof-of-concept trials could accelerate the evaluation of repurposed drugs. Drawing lessons from repurposing efforts for COVID-19 therapies, here we present a vision for a drug repurposing platform that could maximize efficiency and improve patient outcomes for many different conditions.

Mitochondria are involved in many dynamic processes, including their role in the production of the cell's energy currency, adenosine triphosphate (ATP).This production is carried out through a complex chain of chemical reactions, followed by the transition of electrons through four protein clusters on the mitochondrial membrane called respiratory complexes.This transfer drives protons across the membrane creating a high concentration on one side of the membrane.The difference in concentration, known as the mitochondrial membrane potential (MMP), allows the flow of protons through respiratory Complex V to combine adenosine diphosphate with phosphate to create ATP [1].Mitochondrial problems were first discovered in Parkinson's Disease (PD) in the 1980's when drug users injected contaminated heroin and subsequently developed parkinsonian symptoms [2].Further investigation in animal models identified that the contaminant was 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), which was metabolised to 1-methyl-4-phenylpyridinium (MPP+),an inhibitor of mitochondrial respiration [2,3].Inhibition of mitochondrial respiration with MPP+results in reduced ATP levels and the production of harmful reactive oxygen species [4][5][6].Mitochondrial dysfunction in PD was later confirmed when reduced

PGC-1α plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and an RNA recognition motif, however the RNA-processing function(s) were poorly investigated over the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export receptor NXF1. Inducible depletion of PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrate that its RNA/NXF1-binding activity is required for the nuclear export of some canonical mitochondrial-related mRNAs and mitochondrial homeostasis. Genome-wide investigations reveal that the nuclear export function is not strictly linked to promoter-binding, identifying in turn novel regulatory targets of PGC-1α in non-homologous end-joining and nucleocytoplasmic transport. These findings provide new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, aging and neurodegeneration.

An increase in the efficiency of clinical trial conduct has been successfully demonstrated in the oncology field, by the use of multi-arm, multi-stage trials allowing the evaluation of multiple therapeutic candidates simultaneously, and seamless recruitment to phase 3 for those candidates passing an interim signal of efficacy. Replicating this complex innovative trial design in diseases such as Parkinson's disease is appealing, but in addition to the challenges associated with any trial assessing a single potentially disease modifying intervention in Parkinson's disease, a multi-arm platform trial must also specifically consider the heterogeneous nature of the disease, alongside the desire to potentially test multiple treatments with different mechanisms of action. In a multi-arm trial, there is a need to appropriately stratify treatment arms to ensure each are comparable with a shared placebo/standard of care arm; however, in Parkinson's disease there may be a preference to enrich an arm with a subgroup of patients that may be most likely to respond to a specific treatment approach. The solution to this conundrum lies in having clearly defined criteria for inclusion in each treatment arm as well as an analysis plan that takes account of predefined subgroups of interest, alongside evaluating the impact of each treatment on the broader population of Parkinson's disease patients. Beyond this, there must be robust processes of treatment selection, and consensus derived measures to confirm target engagement and interim assessments of efficacy, as well as consideration of the infrastructure needed to support recruitment, and the long-term funding and sustainability of the platform. This has to incorporate the diverse priorities of clinicians, triallists, regulatory authorities and above all the views of people with Parkinson's disease.

The relative contributions of factors such as muscle strength, falls risk and low bone mineral density (BMD) to increased fracture risk in Parkinson's Disease (PD) were examined in an analysis of 5212 community-dwelling women age 75 years or more recruited to a randomised, double-blind, placebo-controlled study of the oral bisphosphonate, clodronate. Similar number of PD and non-PD subjects received treatment. Each participant had measurements of hip and forearm BMD, muscle strength (hand grip strength and maximum isometric quadriceps strength), ability in the sit-to-stand test, and postural stability. Incident radiographic and/or surgically verified fractures, and deaths, were recorded over an average follow-up of 3.8 years. A diagnosis of PD was made if it was self-reported and appropriate medication was recorded at the study entry. 47 of the women (0.9 %) had a diagnosis of PD at baseline. They were of similar age to those without PD, but reported higher disability scores and lower quality of life. While BMD at the forearm and hip regions was lower in PD, this only reached statistical significance at the femoral neck (0.61 +/- 0.12 vs 0.65 +/- 0.12 g/cm2, p = 0.037). Right hand grip strength was non-significantly lower in PD, but maximum right quadriceps strength was much reduced (96.9 +/- 49.3 vs 126.3 +/- 59.2 N, p = 0.003). Eleven (23.4 %) of the women with PD sustained 12 fractures, while 609 women (11.8 %) without PD sustained 742 osteoporotic fractures. The risk of osteoporotic fracture associated with PD was 2.24-fold higher in women with PD (Cox-regression HR 2.24, 95 % CI 1.23-4.06) and this remained high when adjusted for death as a competing risk (2.17, 95 % CI 1.17-4.01, p = 0.013). Following adjustment for femoral neck BMD, PD remained a significant predictor of fracture (HR 2.04, 1.12-3.70, p = 0.020). Entering PD as a risk variable using the rheumatoid arthritis input as a surrogate resulted in a reduction in PD as a FRAX-independent risk factor, particularly when BMD was included in FRAX (1.65, 95 % CI), but the relationship between PD and fracture risk appears to remain of clinical significance. The study suggests that PD may be an independent input in future iterations of FRAX, possibly due to nonskeletal components of risk such as reduced lower limb muscle strength. Introducing measures of muscle strength and performance in FRAX could also be considered.