Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson's disease (PD). Here, we utilized auxilin knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. Auxilin KO mice display cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Significantly, treatment with L-DOPA ameliorated motor deficits. Unbiased proteomic and neurochemical analyses of auxilin KO brains indicated dopamine dyshomeostasis. We validated these findings by demonstrating slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. Defective SV protein sorting and elevated synaptic autophagy also contribute to ineffective dopamine sequestration and compartmentalization, ultimately leading to neurodegeneration. This study provides insights into how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.
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http://dx.doi.org/10.1016/j.celrep.2023.112231 | DOI Listing |
Pharmacol Res Perspect
February 2025
New Drug Development Center, Daegu, Korea.
Oxidation of dopamine can cause various side effects, which ultimately leads to cell death and contributes to Parkinson's disease (PD). To counteract dopamine oxidation, newly synthesized dopamine is quickly transported into vesicles via vesicular monoamine transporter 2 (VMAT2) for storage. VMAT2 expression is reduced in patients with PD, and studies have shown increased accumulation of dopamine oxidation byproducts and α-synuclein in animals with low VMAT2 expression.
View Article and Find Full Text PDFJ Neurochem
January 2025
Department of Pathology, School of Veterinary Medicine, University of São Paulo, Sao Paulo, Brazil.
Autism spectrum disorder (ASD) is a complex developmental disorder characterized by several behavioral impairments, especially in socialization, communication, and the occurrence of stereotyped behaviors. In rats, prenatal exposure to valproic acid (VPA) induces autistic-like behaviors. Previous studies by our group have suggested that the autistic-like phenotype is possibly related to dopaminergic system modulation because tyrosine hydroxylase (TH) expression was affected.
View Article and Find Full Text PDFJ Neuroimaging
January 2025
Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea.
Background And Purpose: We investigated the relationship between serotonergic and dopaminergic specific binding transporter ratios (SBRs) over 4 years in Parkinson's disease (PD) patients. We assessed serotonergic innervation's potential compensatory role for dopaminergic denervation, association with PD symptoms, and involvement in the development of levodopa-induced dyskinesia (LID).
Methods: SBRs of the midbrain and striatum were evaluated from [I-123] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane SPECT images at baseline and after 4 years.
Int J Mol Sci
December 2024
Department of Anatomy, Dokkyo Medical University School of Medicine, 880 Kita-Kobayashi, Mibu-machi, Shimotsuga-gun 321-0293, Tochigi, Japan.
Neuroscience
January 2025
Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran; Department of Physiology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran. Electronic address:
Corticosteroid signaling plays a critical role in modulating the neural systems underlying reward and addiction, but the specific contributions of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the medial prefrontal cortex (mPFC) to opioid reward and dopaminergic plasticity remain unclear. Here, we investigated the effects of intra-mPFC injection of corticosteroid receptor ligand (corticosterone; CORT), glucocorticoid receptor antagonist (RU38486; RU), and mineralocorticoid receptor antagonist (spironolactone; SP) on morphine-induced conditioned place preference (CPP) and dopamine transporter (DAT) expression in the mPFC. Adult male Wistar rats received intra-mPFC injections of CORT, RU, SP, or their respective vehicles prior to morphine CPP conditioning.
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