The Heart of the Matter: Cardiac Denervation Casts Doubt on the Brain‐First Versus Body‐First Hypothesis of Parkinson's Disease

Movement Disorders, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Parkinson's disease (PD) is an increasingly common neurodegenerative that pathologically characterized by preferential dopaminergic cell loss in the substantia nigra (SN) and appearance of Lewy bodies (LBs) other neurons. Braak colleagues1 have shown dorsal motor nucleus vagal nerve (DMV) medulla oblongata olfactory bulb (OB) are two major sites early LB formation. Further, DMV has a higher burden pathology than upper brainstem, including locus coeruleus SN PD. Due to caudorostral gradient brainstem LBs, it been hypothesized pathological process PD begins lower subsequently progresses ascending fashion. This referred as hypothesis.1, 2 Thereafter, Hawkes et al3 refined this concept incorporating peripheral autonomic nervous system (PNS) OB, they proposed in-depth hypothesis neurotoxic pathogens (eg, viruses, pesticides, air pollutants) enter brain via routes enteric (ENS) OB. dual-hit hypothesis. Then, some experimental findings α-synuclein [aS] aggregates propagating from one another) were integrated,4 leading compelling hypothesis, particular, pathophysiology governed unitarily prion-like transmission misfolded aS either or gut (the brain-first vs. body-first hypothesis).5, 6 conceptual framework attracted significant attention with expectation transmissible species could be novel targets neuroprotective therapies such immunotherapy.7 However, notion can explained solely spread noxious remains matter debate8-10 mainly criticized for its oversimplification explanation complexity actual pathology.11 Recently, we reported cardiac sympathetic denervation was associated widespread cortical atrophy, but not nigrostriatal neurodegeneration PD.12 The finding occurs both PNS central (CNS) independent midbrain lesion may support idea multifocal diffuse initiation rather one-way propagation single origin. To address these issues, discuss limitations versus focusing on unique feature involvement. origin site connectome (SOC) model, which Borghammer colleagues,5, 13 recent topical about spreading pathologies In interneuronal aberrantly plays role pathogenesis. addition, phenotypic variability among patients earliest onset neural connections extending those sites. misfolding originates OB and/or amygdala cerebral hemisphere gut. correspond distinct clinicopathological phenotypes PD, subtypes. benign subtype starts unilateral spreads ipsilateral neighboring areas, followed various areas spinal cord PNS. greater asymmetry symptoms predominantly distribution because fewer interhemispheric brain. On contrary, malignant ENS reaches bilateral progression areas.14-16 Compared likely faster due strong bidirectional CNS. Taking step further, rapid eye movement-sleep behavior disorder (RBD), related coeruleus, before parkinsonism indicates (Fig. 1A).6, 13-16 Theoretically, SOC model simple plausible directly links hypotheses prionoid nature aS. based several unproven assumptions (1) at origin, (2) pathogenic propagates exclusively intercellular transmission, (3) RBD arises when pons.5, 13, 16 Furthermore, imaging studies striatal dysfunction provide conflicting evidence against model.9, 17 Moreover, mechanism behind degeneration adequately considered model. Thus, should further discussed. Cardiac distinguishable diseases atypical parkinsonism. nerves interpreted relay points supported Postmortem demonstrated phosphorylated accumulates distal axons neuronal soma paravertebral ganglia.18 simultaneous observations density ganglia more severe intermediolateral (IML) 1B).19, 20 there case incidental restricted heart ganglia.21 These data strongly indicate deposits occur periphery initially, then ganglia, anatomically connected IML. only route IML postganglionic irrespective subtypes, inconsistent human pathology. discrepancy attempts explain neurogenous starting point changes start still enigmatic. parasympathetic nerves, together cholinergic vagus nerve.22-24 pattern seems unlikely dysfunctions independently phase PD24; exceeds DMV,22 suggests precedes PD.25 Recent seeds blood diseases,26, 27 suggesting possibility systemic proteins bloodstream. If exists, addition OB/amygdala ENS, It also pointed out begin part skin or, recently, kidney,28 regardless hematogenous raises question premise adopt spatial gradients guidepost progression. possible caused differences vulnerability nuclei LB,20 determined molecular mechanisms, mitochondrial dysfunction, autophagy-lysosome malfunction, aberrant vesicular transport machinery.29 cerebrospinal fluid, insufficient clearance glymphatic concomitant proteinopathies amyloid β, tau, TDP-43) contribute PD.30-33 brief, now becoming clearer exclusive explaining all neuron-to-neuron logical basis cannot sufficiently Therefore, mechanistic backgrounds, nonneurogenic considered. results nuclear studies, insights into their clinical significance. Postganglionic visualized using 123I-meta-iodobenzylguanidine (123I-MIBG) myocardial scintigraphy. outcome measures include delayed heart-to-mediastinum (H/M) ratios 123I-MIBG uptake anterior planar images calculated 15–30 minutes 3–4 hours after radiotracer injection, respectively, washout rate (WR), represents ratio between scans, assessed.34 MIBG abnormality robust marker LBDs, abnormal scan included diagnostic criteria DLB.35, 36 noted familial forms PARK-PARKIN PARK-LRRK2, show pure nigral without retain uptake.37 multiple atrophy present slight abnormalities association neurodegeneration. differential diagnosis specificity sensitivity scintigraphy >80% approximately 70%–90%, respectively.35, 36, 38, 39 A validation study H/M shows highest discriminate LBDs non-LBDs WR, standardized cutoff values.40 Despite high specificity, stages late PD.38 existence subgroups observed advanced stages, stages. By contrast, beginning symptoms.16 view Based notions, recently conducted developed biological subtypes according biomarkers, scintigraphy.12 We investigated whether classified meaningful duration any consideration findings. As result, identified. One severity, cardio-cortical impairment subtype. terminal compared less even dopaminergic-dominant Our method aimed classify extradopaminergic classification does accurately reflect relevant reached below de novo stage Horsager al,16 nearly half exhibited stage, clearly contradicts cast doubt Idiopathic (iRBD) prodromal subtype,41-43 corroborating body-to-brain Indeed, iRBD frequently along reduced uptake, body often accompanied cognitive impairment, indicating involvement.41, 44 suggest broader regions beyond focal lesions, arousing suspicion Taken together, arguments PD.16 ensures better understanding pathogenesis improve trial designs development disease-modifying therapies. attempt terms inter-neuronal attention. provided pathophysiological background become evident oversimplified pathology, particularly considering involvement system. Other models, protein misfolding, promising T. Totsune receives Grants-in-Aid Scientific Research Japanese Society Promotion Sciences (24K02656) honoraria lectures Nihon Medi-physics Co., Ltd., Kyowa Kirin Co. Takeda Pharmaceutical Ltd. Baba research grants Ltd Ono AbbVie Inc., Eizai Hasegawa (23K06823). A. scholarship funds Eisai Sumitomo Pharma Ltd.; consulting fees Sony Co.; project: Conception, B. Organization, C. Execution; Manuscript: Writing first draft, Review critique. T.T.: 1A, 1C, 2A. T.B.: 2B. T.H.: A.T.: 1B, Data sharing applicable article no new created analyzed study.

Language: Английский

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Dynactin knockdown leads to synuclein aggregation by blocking autophagy in a zebrafish model of Parkinson's disease

Brazilian Journal of Medical and Biological Research, Journal Year: 2025, Volume and Issue: 58

Published: Jan. 1, 2025

Axons of dopaminergic neurons projecting from substantia nigra to striatum are severely affected in the early stage Parkinson's disease (PD), with axonal degeneration preceding loss cell bodies. Our previous study indicated that dysfunctional retrograde transport could lead death resulting PD (10.1111/j.1471-4159.2008.05526.x). However, dynein, as main molecule involved transport, was not affected. This aimed verify hypothesis dynactin rather than dynein may be one key factors PD. Dynactin morpholino used inhibit expression transgenic (Vmat2:GFP) zebrafish, a significant decrease diencephalon dopamine and synuclein aggregation basal plate region. In SH-SY5Y line, dynactin-siRNA knockdown resulted shifting dispersed distribution concentration synapses cytoplasm near axons, fusion rate decreased, especially which blocked α-synuclein autophagy flow. results linked gene dysfunction microtubule system, suggesting contributing

Language: Английский

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Effectiveness of mesenchymal stem cell-derived extracellular vesicles therapy for Parkinson’s disease: A systematic review of preclinical studies

World Journal of Stem Cells, Journal Year: 2025, Volume and Issue: 17(4)

Published: April 21, 2025

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can traverse the blood-brain barrier due to their small size. This characteristic makes them a research hotspot for treatment of Parkinson's disease (PD) and is expected be potentially revolutionary strategy treating PD. Despite this, no summary clinical trial results has been reported. To assess efficacy durability MSC-EVs in Systematic searches were conducted four electronic databases until June 2024 collect studies on use this purpose. Thirteen relevant randomized controlled trials, encompassing 16 experiments, selected inclusion. Behavioral assessments, including rotarod apomorphine turning behavior tests, indicated improvements motor coordination (P < 0.00001); Pole test Wire-hang showed enhanced limb agility synchronization = 0.003 P 0.00001, respectively). Histopathologically, there was reduction inflammatory markers such as tumor necrosis factor-α interleukin-6 0.03 0.01, respectively) an increase tyrosine hydroxylase-positive cells lesion areas 0.00001). MSC-EV therapy PD gradual process, with significant observable more than 2 weeks after administration lasting at least 8 weeks. study first demonstrate

Language: Английский

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The Association Between Essential Tremor and Parkinson’s Disease: A Systematic Review of Clinical and Epidemiological Studies

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(8), P. 2637 - 2637

Published: April 11, 2025

Background/Objectives: The objective is to systematically review evidence from clinical and epidemiological studies for or against an association between essential tremor (ET) Parkinson’s disease (PD). Methods: A literature search in PubMed (February 2025) used several combinations of keywords. Thirty-three (1960–2023) were identified. Results: best available data are derived a population-based study Spain, followed by cohort the US. Each these prospective provided that ET risk factor PD, with elevated risks ~4–5. In cross-sectional studies, which proportion PD cases has been reported, weight demonstrates PD. 16 (88.9%) 18 family odds ratios hazards elevated—i.e., there considerable over-represented families and, conversely, families. Conclusions: comprehensive published strongly supports more specifically, provides Seven nine articles (and six seven non-commissioned articles) have concluded two degenerative diseases. “controversy” surrounds ET–PD repeated myth than well-informed reality. As field, it would be productive finally move beyond uniformed debate focus our efforts on attempts elucidate basis repeatedly pointing.

Language: Английский

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Dopamine and cortical iPSC-derived neurons with different Parkinsonian mutations show variation in lysosomal and mitochondrial dysfunction: implications for protein deposition versus selective cell loss

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 11, 2024

Abstract Background Mutations causing Parkinson’s disease (PD) give diverse pathological phenotypes whose cellular correlates remain to be determined. For example, those with PRKN loss of function mutations have significantly earlier selective vulnerability dopamine neurons, SNCA increased alpha-synuclein deposition, while LRRK2 additional deposition tau. Yet all three mutation types are implicated in mitochondrial and/or lysosomal dysfunction. Direct comparison cell models these would clarify the relative dysfunctions associated different phenotypes. Methods An unbiased high-content imaging platform using orthogonal probes assess both and dysfunction, along tau protein was established induced pluripotent stem (iPSC) derived cortical ventral midbrain neurons. Three types, A53T, R1441G (lof), were selected as exemplars divergent PD compared each other, control iPSC from subjects without PD. Results Different caused type specific dysfunctions, likely impact on neuronal pathologies observed Comparison neurons identified that dysfunction predominant lof mutations, whereas immunofluorescent staining revealed A53T had deposition. In contrast, autophagy impairments cells additionally showing decreased glucocerebrosidase activity phosphorylation. Conclusions Lysosomal may drive early carriers. More subtle abnormalities lines predispose aggregation over time. The also but despite substantial phosphorylation, accumulations not observed. Understanding mechanistic differences how pathogenesis subtypes important for therapeutic development.

Language: Английский

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Allosteric Activation of SIRT1 by 2,4-Dihydroxy-azaflavanone Averts MPP⁺-Mediated Dysfunction in Mitochondrial Biogenesis and Bioenergetics: Implications for Parkinson’s Disease

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(15), P. 2870 - 2883

Published: July 29, 2024

Parkinson's disease (PD) is a complex neurodegenerative disorder that affects dopamine neurons of the substantia nigra pars compacta (SNpc), resulting in motor dysfunction. Among pathways examined, mitochondria and α-synuclein were found to play major role progression. Hence, several attempts are being made restore mitochondrial bioenergetics or protein aggregation as disease-modifying strategies. Our earlier studies reported protective effect 2,4-dihydroxy-azaflavanone (azaflavanone) transgenic Drosophila fly model PD. In present study, we azaflavanone acts an allosteric activator SIRT1 both cell-free cell-based systems effects more pronounced compared resveratrol. Also, appears interact selectively with other SIRTs such SIRT3 SIRT6 did not exhibit any gross changes cellular thermal shift assay (CETSA). Molecular docking depicted higher score than Further, N27 cells treated exhibited dose-dependent increase mitotracker staining, mtDNA/nuclear DNA ratio, also bioenergetics. The observed appear be due activation SIRT1, evidenced by expression PGC-1α TFAM, which downstream targets SIRT1. Lastly, Parkinsonian mimic MPP+-induced disturbance membrane potential, bioenergetics, biogenesis ameliorated azaflavanone. Overall, our findings indicate azaflavanone, antioxidant promising compound for ameliorating pathophysiology

Language: Английский

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Effect of 5-alpha reductase inhibitors in animal models of Parkinson’s disease

Frontiers in Neuroendocrinology, Journal Year: 2024, Volume and Issue: unknown, P. 101156 - 101156

Published: Sept. 1, 2024

Language: Английский

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The GBA1 K198E Variant Is Associated with Suppression of Glucocerebrosidase Activity, Autophagy Impairment, Oxidative Stress, Mitochondrial Damage, and Apoptosis in Skin Fibroblasts

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9220 - 9220

Published: Aug. 25, 2024

Parkinson’s disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as result of the loss dopaminergic (DAergic) neurons pars compacta in substantia nigra protein aggregates alpha synuclein (α-Syn). Although its etiopathology agent has not yet been clearly established, environmental genetic factors have suggested major contributors to disease. Mutations glucosidase beta acid 1 (GBA1) gene, which encodes lysosomal glucosylceramidase (GCase) enzyme, are one risks for PD. We found that GBA1 K198E fibroblasts but WT showed reduced catalytic activity heterozygous mutant GCase by −70% expression levels increased 3.68-fold; acidification autophagy vacuoles (e.g., autophagosomes, lysosomes, autolysosomes) +1600%; augmented autophagosome Beclin-1 (+133%) LC3-II (+750%), lysosomal–autophagosome fusion LAMP-2 (+107%); accumulation lysosomes (+400%); decreased mitochondrial membrane potential (∆Ψm) −19% Parkin remained unperturbed; oxidized DJ-1Cys106-SOH +900%, evidence oxidative stress; phosphorylated LRRK2 at Ser935 (+1050%) along with α-synuclein (α-Syn) pathological residue Ser129 (+1200%); executer apoptotic caspase 3 (cleaved 3) +733%. exposure neutoxin rotenone (ROT, μM) exacerbated autophagy–lysosomal system, stress, apoptosis markers, ROT moderately those markers fibroblasts. concluded mutation endogenously primes skin toward dysfunction, OS, apoptosis. Our findings suggest biochemically molecularly equivalent response exposed ROT.

Language: Английский

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Analysis of dopaminergic neuron-specific mitochondrial morphology and function using tyrosine hydroxylase reporter iPSC lines

Anatomical Science International, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 29, 2024

Language: Английский

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