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The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA-OVX) that express wild-type α-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous α-synuclein. SNCA-OVX mice display age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype is preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits are not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits are associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged SNCA-OVX mice exhibit reduced firing of SNc dopamine neurons in vivo measured by juxtacellular recording of neurochemically identified neurons. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting neurophysiological changes precede, and are not driven by, aggregate formation. This longitudinal phenotyping strategy in SNCA-OVX mice thus provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.
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http://dx.doi.org/10.1073/pnas.1309143110 | DOI Listing |
Protein Sci
January 2025
Institut de Biotecnologia i de Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain.
Peptides are attracting a growing interest for therapeutic applications in biomedicine. In Parkinson's disease (PD), different human endogenous peptides have been associated with beneficial effects, including protein aggregation inhibition, reduced inflammation, or the protection of dopaminergic neurons. Such effects seem to be connected to the spatial arrangement of peptide side chains, and many of these human molecules share common conformational traits, displaying a distinctive amphipathic and cationic helical structure, which is believed to be crucial for their activities.
View Article and Find Full Text PDFiScience
December 2024
Department of Biomedical and Clinical Sciences, Department of Clinical Pathology, Linköping University, Linköping, Sweden.
Accumulating evidence demonstrates that alpha-synuclein (α-syn) pathology associated with Parkinson's disease (PD) is not limited to the brain, as it also appears in a select number of peripheral tissues including the liver. In this study, we identified a number of PD-associated α-syn post-translational modifications in the livers of (Thy-1)-h[A30P] mice, a mouse model of familial PD expressing human α-syn harboring the A30P mutation driven by a neuron-specific promoter. , we also demonstrate that human hepatocytes induce post-translational modifications following α-syn fibrillar (PFF) treatment.
View Article and Find Full Text PDFiScience
December 2024
Department of Materials Science, Faculty of Science, Srinakharinwirot University, Sukhumvit 23, Watthana, Bangkok 10110, Thailand.
Parkinson's disease (PD) prevalence is projected to reach 12 million by 2040. Wearable sensors offer a promising approach for comfortable, continuous tremor monitoring to optimize treatment strategies. Here, we present a wristwatch-like triboelectric sensor (WW-TES) inspired by automatic watches for unobtrusive PD tremor assessment.
View Article and Find Full Text PDFFront Aging Neurosci
December 2024
Department of Neurology, University of Regensburg Hospital, Regensburg, Germany.
Front Neurol
December 2024
Henan Academy of Innovations in Medical Science, Brain Institute, Zhengzhou, China.
Parkinson's disease (PD) is a chronic, progressive neurological disorder primarily affecting motor control, clinically characterized by resting tremor, bradykinesia, rigidity, and other symptoms that significantly diminish the quality of life. Currently, available treatments only alleviate symptoms without halting or delaying disease progression. There is a significant association between PD and type 2 diabetes mellitus (T2DM), possibly due to shared pathological mechanisms such as insulin resistance, chronic inflammation, and mitochondrial dysfunction.
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