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Objective: The motor severity in Parkinson disease (PD) is believed to parallel dopaminergic terminal degeneration in the striatum, although the terminal was reported to be virtually absent by 4 years postdiagnosis. Meanwhile, neuromelanin‐laden dopamine neuron loss in the substantia nigra (SN) elucidated a variability at early stages and gradual loss with less variability 10 years postdiagnosis. Here, we aimed to clarify the correlation between motor impairments and striatal dopaminergic terminal degeneration and nigral neuromelanin‐laden dopamine neuron loss at early to advanced stages of PD. Methods: Ninety‐three PD patients were divided into early and advanced subgroups based on motor symptom duration and whether motor fluctuation was present. Striatal dopaminergic terminal degeneration was evaluated using a presynaptic dopamine transporter tracer, 123I‐ioflupane single photon emission computed tomography (SPECT). Nigral neuromelanin‐laden dopamine neuron density was assessed by neuromelanin‐sensitive magnetic resonance imaging (NM‐MRI). Results: In patients with early stage PD (motor symptoms for ≤8 or 10 years), motor dysfunction during the drug‐off state was paralleled by a decline in 123I‐ioflupane uptake in the striatum despite the absence of a correlation with reductions in NM‐MRI signals in SN. Meanwhile, in patients with advanced stage PD (motor symptoms for >8 or 10 years and with fluctuation), the degree of motor deficits during the drug‐off state was not correlated with 123I‐ioflupane uptake in the striatum, despite its significant negative correlation with NM‐MRI signals in SN. Interpretation: We propose striatal dopaminergic terminal loss measured using 123I‐ioflupane SPECT and nigral dopamine neuron loss assessed with NM‐MRI as early stage and advanced stage motor impairment biomarkers, respectively. ANN NEUROL 2022;92:110–121 [ABSTRACT FROM AUTHOR]

Background: The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity. Objective: The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α‐synuclein transmission in cultured cells and mouse models of Parkinson's disease. Methods: Mouse primary hippocampal neurons were transduced with α‐synuclein preformed fibrils to examine the effect of perampanel on the development of α‐synuclein pathology and its mechanisms of action. An α‐synuclein preformed fibril‐injected mouse model was used to validate the effect of oral administration of perampanel on the α‐synuclein pathology in vivo. Results: Perampanel inhibited the development of α‐synuclein pathology in mouse hippocampal neurons transduced with α‐synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α‐synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity‐dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α‐synuclein pathology in wild‐type mice inoculated with α‐synuclein preformed fibrils. Conclusion: Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease‐modifying drug for Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Abstract: Kufor-Rakeb syndrome (KRS) was originally described as an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia. ATP13A2 was identified as the causative gene in KRS. ATP13A2 encodes the ATP13A2 protein, which is a lysosomal type5 P-type ATPase, and ATP13A2 mutations are linked to autosomal recessive familial parkinsonism. Here, we report that normal ATP13A2 localizes in the lysosome, whereas disease-associated variants remain in the endoplasmic reticulum. Cathepsin D activity was decreased in ATP13A2-knockdown cells that displayed lysosome-like bodies characterized by fingerprint-like structures. Furthermore, an atp13a2 mutation in medaka fish resulted in dopaminergic neuronal death, decreased cathepsin D activity, and fingerprint-like structures in the brain. Based on these results, lysosome abnormality is very likely to be the primary cause of KRS/PARK9. [Copyright &y& Elsevier]