Synaptic, Mitochondrial, and Lysosomal Dysfunction in Parkinson’s Disease

Nguyen, Maria; Wong, Yvette C.; Ysselstein, Daniel; Severino, Alex; Krainc, Dimitri

doi:10.1016/j.tins.2018.11.001

Cited by 236 publications

(185 citation statements)

References 89 publications

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“…66 In addition, given that homozygous mutations in synj1 have also been linked to early-onset, atypical PD, mouse models carrying this mutation also demonstrate defective synaptic vesicle endocytosis as well as a surprising increase in both auxilin and parkin levels, 177 further suggesting that multiple PD genes may converge on defective synaptic vesicle endocytosis. 178…”

Section: Other Implicated Genes That Play a Role In Synaptic Vesiclementioning

confidence: 99%

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

et al. 2019

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While current effective therapies are available for the symptomatic control of PD, treatments to halt the progressive neurodegeneration still do not exist. Loss of dopamine neurons in the SNc and dopamine terminals in the striatum drive the motor features of PD. Multiple lines of research point to several pathways which may contribute to dopaminergic neurodegeneration. These pathways include extensive axonal arborization, mitochondrial dysfunction, dopamine's biochemical properties, abnormal protein accumulation of α‐synuclein, defective autophagy and lysosomal degradation, and synaptic impairment. Thus, understanding the essential features and mechanisms of dopaminergic neuronal vulnerability is a major scientific challenge and highlights an outstanding need for fostering effective therapies against neurodegeneration in PD. This article, which arose from the Movement Disorders 2018 Conference, discusses and reviews the possible mechanisms underlying neuronal vulnerability and potential therapeutic approaches in PD. © 2019 International Parkinson and Movement Disorder Society

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Section: Other Implicated Genes That Play a Role In Synaptic Vesiclementioning

confidence: 99%

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

et al. 2019

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“…Furthermore, bottom‐up disease progression hardly justifies the typical focal presentation of PD at clinical onset, because no somatotopy has been recognized in the SNc. Increasing evidence points toward striatal onset of nigrostriatal loss, starting from the axons rather than the somas of nigrostriatal neurons, although the possibility that dysfunction at the soma could compromise axonal flow and synaptic degeneration should not be ruled out as yet . Indeed, the option of a dual, distal synaptic mechanism associated with proximal soma abnormalities is a plausible, if not likely, current assumption to understand the onset of nigrostriatal neurodegeneration .…”

Section: When Where and How To Apply Focused Ultrasound For Diseasementioning

confidence: 99%

“…Increasing evidence points toward striatal onset of nigrostriatal loss, starting from the axons rather than the somas of nigrostriatal neurons, 33,[39][40][41] although the possibility that dysfunction at the soma could compromise axonal flow and synaptic degeneration should not be ruled out as yet. 42 Indeed, the option of a dual, distal synaptic mechanism associated with proximal soma abnormalities is a plausible, if not likely, current assumption to understand the onset of nigrostriatal neurodegeneration. 43 Building mainly on the concept of retrograde nigrostriatal neurodegeneration, we recently proposed a top-down pathogenesis in which corticostriatal activity might represent a critical somatotopic "stressor" for nigrostriatal terminals, ultimately leading to focal motor onset and progression of PD.…”

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confidence: 99%

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

et al. 2019

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A major unmet need in Parkinson's disease (PD) is to slow the inexorable progression of neurodegeneration. Clinical trials that evaluated promising pharmacological strategies have repeatedly failed. Nonetheless, the advent of focused ultrasound provides new opportunities toward the goal of developing a safe and effective disease‐modifying therapy for PD. Here we discuss the rationale, possible avenues, and challenges along this path, exploiting the potential of focused ultrasound for (1) performing focal thermal lesions to restore the basic basal ganglia abnormalities associated with dopamine depletion, and (2) transiently opening the blood–brain barrier for targeted delivery of therapeutic agents. First, the classic idea of excitotoxicity mediated by hyperactivity of the subthalamic nucleus suggests that focused ultrasound subthalamotomy may offer a clinically viable disease‐modifying therapy in very‐early PD. Second, the concept of retrograde nigrostriatal neurodegeneration, supported by our recent cortical pathogenic theory of PD, points toward the putamen as a principal site for focused ultrasound blood–brain barrier opening and targeted drug delivery. In principle, both therapeutic strategies—subthalamotomy and putaminal blood–brain barrier opening—could eventually be applied in the same patient. Clinical application is still a long road ahead; nevertheless, focused ultrasound may open a twofold path toward disease modification in PD. © 2019 International Parkinson and Movement Disorder Society

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“…Aging represents the most crucial event, linking increased inflammation and oxidative stress to mitochondrial dysfunction and dysregulation of lysosomal, proteosomal and autophagic functions, likely contributing to the chronic neuronal deterioration in the PD brain (Boger, Granholm, McGinty, & Middaugh, ; Dzamko et al, ; Giguère, Burke Nanni, & Trudeau, ; Marchetti & Abbracchio, ; McGeer & McGeer, ; Nguyen et al, ; Surmeier, ). Hence, with advancing age, the nigrostriatal DAergic system progressively declines and the adaptive/compensatory DAergic potential gradually fails, leading to the slow but inexorable nigrostriatal degeneration of PD with the late appearance of clinical signs (Bezard & Gross, ; Collier et al, ; de la Fuente‐Fernández et al, ; Hindle, ; Hornykiewicz, ; Obeso et al, ).…”

Section: Introductionmentioning

confidence: 99%

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

et al. 2020

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A common hallmark of age‐dependent neurodegenerative diseases is an impairment of adult neurogenesis. Wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling is a vital pathway for dopaminergic (DAergic) neurogenesis and an essential signalling system during embryonic development and aging, the most critical risk factor for Parkinson's disease (PD). To date, there is no known cause or cure for PD. Here we focus on the potential to reawaken the impaired neurogenic niches to rejuvenate and repair the aged PD brain. Specifically, we highlight WβC‐signalling in the plasticity of the subventricular zone (SVZ), the largest germinal region in the mature brain innervated by nigrostriatal DAergic terminals, and the mesencephalic aqueduct‐periventricular region (Aq‐PVR) Wnt‐sensitive niche, which is in proximity to the SNpc and harbors neural stem progenitor cells (NSCs) with DAergic potential. The hallmark of the WβC pathway is the cytosolic accumulation of β‐catenin, which enters the nucleus and associates with T cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, leading to the transcription of Wnt target genes. Here, we underscore the dynamic interplay between DAergic innervation and astroglial‐derived factors regulating WβC‐dependent transcription of key genes orchestrating NSC proliferation, survival, migration and differentiation. Aging, inflammation and oxidative stress synergize with neurotoxin exposure in “turning off” the WβC neurogenic switch via down‐regulation of the nuclear factor erythroid‐2‐related factor 2/Wnt‐regulated signalosome, a key player in the maintenance of antioxidant self‐defense mechanisms and NSC homeostasis. Harnessing WβC‐signalling in the aged PD brain can thus restore neurogenesis, rejuvenate the microenvironment, and promote neurorescue and regeneration.

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Synaptic, Mitochondrial, and Lysosomal Dysfunction in Parkinson’s Disease

Cited by 236 publications

References 89 publications

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

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