Emerging perspectives of synaptic biomarkers in ALS and FTD

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: Jan. 5, 2024

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are debilitating neurodegenerative diseases with shared pathological features like transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions genetic mutations. Both involve synaptic dysfunction, contributing to their clinical features. Synaptic biomarkers, representing proteins associated function or structure, offer insights into disease mechanisms, progression, treatment responses. These biomarkers can detect early, track its evaluate therapeutic efficacy. ALS is characterized by elevated neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) blood, correlating progression. TDP-43 another key biomarker, mislocalization linked dysfunction. In FTD, tau studied as biomarkers. neuronal pentraxins (NPs), including pentraxin 2 (NPTX2), receptor (NPTXR), FTD pathology cognitive decline. Advanced technologies, machine learning (ML) artificial intelligence (AI), aid biomarker discovery drug development. Challenges this research include technological limitations detection, variability across patients, translating findings from animal models. ML/AI accelerate analyzing complex data predicting outcomes. early personalized strategies, mechanisms. While challenges persist, advancements interdisciplinary efforts promise revolutionize the understanding management FTD. This review will explore present comprehension discuss significance emphasize prospects obstacles.

Language: Английский

Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 31, 2024

Abstract A growing body of knowledge implicates perturbed RNA homeostasis in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that currently has no cure and few available treatments. Dysregulation the multifunctional RNA-binding protein TDP-43 is increasingly regarded as convergent feature this disease, evidenced at neuropathological level by detection pathology most patient tissues, genetic identification disease-associated mutations its coding gene TARDBP . To characterize transcriptional landscape induced mutations, we performed whole-transcriptome profiling motor neurons differentiated from two knock-in iPSC lines expressing ALS-linked variants p.A382T or p.G348C. Our results show significantly altered expression profiles mRNAs microRNAs 14q32 cluster MNs. Using mutation-induced signatures Connectivity Map database, identified compounds predicted to restore toward wild-type levels. Among top-scoring selected for further investigation, NEDD8-activating enzyme inhibitor MLN4924 effectively improved cell viability neuronal activity, highlighting possible role post-translational modification via NEDDylation pathobiology ALS.

Language: Английский