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L1-silenced iPSC line (HS1_L1HS-CRISPRi_g1)
onHuman iPSCs were modified with CRISPRi to target LINE-1 retrotransposons, creating stable cell lines with different genetic backgrounds and guide RNAs. These resources are detailed in Adami et al. (DOI: 10.1016/j.xgen.2025.100979).
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L1-silenced iPSC line (HS1_L1HS-CRISPRi_g2 )
onHuman iPSCs were modified with CRISPRi to target LINE-1 retrotransposons, creating stable cell lines with different genetic backgrounds and guide RNAs. These resources are detailed in Adami et al. (DOI: 10.1016/j.xgen.2025.100979).
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L1-silenced iPSC line – Control (HS1_L1HS-CRISPRi_LacZ )
onHuman iPSCs were modified with CRISPRi to target LINE-1 retrotransposons, creating stable cell lines with different genetic backgrounds and guide RNAs. These resources are detailed in Adami et al. (DOI: 10.1016/j.xgen.2025.100979).
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L1-silenced iPSC line (HS2_L1HS-CRISPRi_g1)
onHuman iPSCs were modified with CRISPRi to target LINE-1 retrotransposons, creating stable cell lines with different genetic backgrounds and guide RNAs. These resources are detailed in Adami et al. (DOI: 10.1016/j.xgen.2025.100979).
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L1-silenced iPSC line (HS2_L1HS-CRISPRi_LacZ)
onHuman iPSCs were modified with CRISPRi to target LINE-1 retrotransposons, creating stable cell lines with different genetic backgrounds and guide RNAs. These resources are detailed in Adami et al. (DOI: 10.1016/j.xgen.2025.100979).
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α-Synuclein Promotes Neuronal Dysfunction and Death by Disrupting the Binding of Ankyrin to β-Spectrin
onα-Synuclein plays a key role in the pathogenesis of Parkinson's disease and related disorders, but critical interacting partners and molecular mechanisms mediating neurotoxicity are incompletely understood. We show that α-synuclein binds directly to β-spectrin. Using males and females in a Drosophila model of α-synuclein-related disorders, we demonstrate that β-spectrin is critical for α-synuclein neurotoxicity. Further, the ankyrin binding domain of β-spectrin is required for α-synuclein binding and neurotoxicity. A key plasma membrane target of ankyrin, Na+/K+ ATPase, is mislocalized when human α-synuclein is expressed in Drosophila Accordingly, membrane potential is depolarized in α-synuclein transgenic fly brains. We examine the same pathway in human neurons and find that Parkinson's disease patient-derived neurons with a triplication of the α-synuclein locus show disruption of the spectrin cytoskeleton, mislocalization of ankyrin and Na+/K+ ATPase, and membrane potential depolarization. Our findings define a specific molecular mechanism by which elevated levels of α-synuclein in Parkinson's disease and related α-synucleinopathies lead to neuronal dysfunction and death.SIGNIFICANCE STATEMENT The small synaptic vesicle associate protein α-synuclein plays a critical role in the pathogenesis of Parkinson's disease and related disorders, but the disease-relevant binding partners of α-synuclein and proximate pathways critical for neurotoxicity require further definition. We show that α-synuclein binds directly to β-spectrin, a key cytoskeletal protein required for localization of plasma membrane proteins and maintenance of neuronal viability. Binding of α-synuclein to β-spectrin alters the organization of the spectrin-ankyrin complex, which is critical for localization and function of integral membrane proteins, including Na+/K+ ATPase. These finding outline a previously undescribed mechanism of α-synuclein neurotoxicity and thus suggest potential new therapeutic approaches in Parkinson's disease and related disorders
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Structural basis for binding of RILPL1 to TMEM55B reveals a lysosomal platform for adaptor assembly through a conserved TBM motif
onInherited mutations in VPS35 and LRRK2 cause Rab GTPase hyperphosphorylation. TMEM55B on lysosomes interacts with RILPL1 through a specific motif, forming complexes with various proteins, revealing new insights into lysosomal function.
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Neuromodulator control of energy reserves in dopaminergic neurons
onNeurons, are vulnerable to metabolic changes. Dopamine helps regulate glycogen storage providing resilience to stress. Loss of this regulation can make dopamine neurons hypersensitive to fuel deprivation, potentially leading to neurodegeneration.
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RNA scope for ATP10b
onProtocol for RNAscope® in situ hybridization on fixed-frozen mouse brain tissue using the RNAscope® Multiplex Fluorescent v2 kit. Includes staining steps for dorsal striatum, sample preparation, and cryosectioning.
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Integrated Representations of Threat and Controllability in the Lateral Frontal Pole
onEmotions can strongly influence behavior, as seen in PD paradoxical kinesia. Here, we demonstrate that anticipating threats enhances motor accuracy through interactions between the amygdala and the anterior pole of the lateral prefrontal cortex.
