Aberrant protein secretion of astrocytes promotes neurodegeneration in α synucleinopathies
Abstract
The α-Synucleinopathies (ASP) that are characterized by abnormal accumulation of insoluble α-synuclein fibrils in neurons and glial comprise neurodegenerative disorders such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). Astrocytes may play a crucial function in ASP, as they show cytoplasmic α-synuclein inclusions and a proinflammatory activated in these diseases. However, the pathological role of α-synuclein in astrocytes remains largely unknown. Here, we show that α-synuclein PFF induce pathogenic activation of mouse primary astrocytes characterized by neuroinflammatory response and non-cell autonomous neuronal toxicity. To identifie the functional regulator of α-synuclein PFF-induced non-cell autonomous neurtoxicity, we performed a secretome analysis with α-synuclein PFF treated Astrocyte-conditioned media. We further identified that knockdown of 7 candidate genes significantly mitigates α-synuclein PFF-induced non-cell autonomous neuronal toxicity. Moreover, A significnat increase was observed in the brain tissue of patients with PD in 4 out of 7 candidate genes. Taken together, our data indicate that the pathogenic alteration in astrocyte-secreted proteins is implicated in the neurodegeneration in α synucleinopathies.
[This work was supported by the KBRI Research Program of the Ministry of Science, ICT & Future Planning (22-BR-02-03, 22-BR-02-04); the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (NRF-2020R1A2C4002366); and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, South Korea (grant number: HI14C1135)]
Unraveling the roles of m6A modification for mRNA localization during axogenesis in the developing cortex
Abstract
Proper development of the nervous system is critical for its function, and deficits in neural development have been implicated in many brain disorders. Recent discoveries of widespread mRNA chemical modifications raise the question of whether this mechanism plays a post-transcriptional regulatory role in the development and function of the brain. N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification that controls various aspects of mRNA metabolism, including stability, translation, splicing, and localization. Neurons are distinctly polarized cells where mRNA can be transported and localized in distal structures like axons and dendrites. However, how m6A modification influences such RNA localization in developing neurons has not been understood well. Here, we showed that Mettl14 deletion in postmitotic neurons resulted in diminished m6A content and impaired axonal projection during corticogenesis. RNA-seq analysis and single-molecule in situ hybridization experiments revealed subsets of mRNA targets were mislocalized in the neurites of postmitotic neurons with m6A loss-of-function. Further, we identified YTHDF2 as the reader protein responsible for mRNA transportation and localization in interhemispheric callosal axons in the developing brain. Our study will enlighten the epitranscriptomic mechanism to regulate axon projection and guidance in during mammalian cortical neurogenesis.
Comparative multi-proteomics approaches for understanding Alzheimer’s disease
Abstract
Discovery of molecular signatures that make it possible to understand diseases have been relatively insufficient. Mass spectrometry-based Omics technologies such as proteomics and metabolomics are widely applied for the identification and characterization of new molecular signatures. Neuronal degeneration damaged by neuronal plaques such as amyloid plaque interferes with the function of neural circuits. Diagnostics of Alzheimer’s disease (AD) is still difficult by using clinically available methods such as clinical exams and amyloid plaque imaging. Those situations are majorly originated by insufficient biological understanding which cannot provide notable molecular mechanisms to explain AD progression. To find new molecular signatures that can explain the molecular pathology of AD, we performed multi-proteomics analysis for age-dependent AD model mice as well as metabolic dysregulated brain cell model. According to subsequent experiments, we found new molecular signatures which can help understand AD. I will introduce those results with recent technological advances.
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