Posttranscriptional regulation of neurofilament proteins and tau in health and disease

Neurofilaments in health and Charcot-Marie-Tooth disease

“…Post-transcriptional regulations are RNA-mediated mechanisms that control many aspects of RNA life, including biogenesis, alternative splicing, stability, transport and translation efficiency. For NFs, post-transcriptional modifications have been found to be triggered by microRNAs (miRNAs) and RNA-binding proteins (RBPs) ( Yuan and Nixon, 2023 ). Collectively, these regulatory mechanisms ensure a spatio-temporal expression of isoforms in specific neuronal compartments and are therefore essential for neuronal physiology.…”

“…Collectively, these regulatory mechanisms ensure a spatio-temporal expression of isoforms in specific neuronal compartments and are therefore essential for neuronal physiology. While miRNAs represent a common mechanism that is deregulated in neurodegenerative diseases ( Juźwik et al, 2019 ), increasing evidence shows the direct role of RNA-mediated mechanisms in the pathophysiology of various neurodegenerative diseases, with dozens of RBP identified as causal genes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) alone ( Yuan and Nixon, 2023 ). Regarding NF mRNAs, the conserved 3′UTR seems to serve as a hub for modifications, as many RBPs (TDP43 ( Strong et al, 2007 ), 14-3–3 ( Miao et al, 2013 ), Aldolase A/C ( Cañete-Soler et al, 2005 ), FUS ( Lagier-Tourenne et al, 2012 ) bind to this region to either stabilise, destabilise or modulate the mRNA of NF-L, NF-M and NF-H. MiRNAs (miR-b1336 ( Ishtiaq et al, 2014 ), MiR-146a ( Campos-Melo et al, 2013 ), miR-233-3p ( Campos-Melo et al, 2018 ), whose biogenesis can be controlled by RBPs, also bind to the 3′UTR regions of the NF mRNAs.…”

Dissecting neurofilament tail sequence-phosphorylation-structure relationships with multicomponent reconstituted protein brushes

“…The three best-studied NF subunits are NF-Light, -Medium, and -Heavy (NFL, NFM, and NFH), and the tail domains of these subunits are highly charged and variable in length. Neurons tune NF function not only by differentially regulating the subunits at transcriptional and post-transcriptional levels 13 , but also by multisite phosphorylation, especially at repetitive lysine-serine-proline (KSP) motifs targeted by various proline-directed kinases. The availability of these phosphorylation motifs varies by subunit; for example, the rat NFM tail sequence contains 5 KSP motifs, while the rat NFH tail contains 52 such motifs 2,14 .…”

Editorial: Cytoskeletal alterations in aging and disease

“…However, the underlying molecular mechanisms require further studies so that we may know how to regulate these PTMs, which can be a double-edged sword for neurons. In this context, the review by Kotaich et al pointed out that the dynamicity of neurofilaments, which is based on their fine-tuned assembly/transport/degradation to sustain key structural and electrophysiological properties of the neurons, is critically influenced by PTMs ( Yuan et al, 2017 ; Yuan and Nixon, 2023 ). These data shed new perspectives on the etiology and treatment of neurofilament-related neurodegenerative disorders (e.g., CMT or amyotrophic lateral sclerosis, ( Rao and Nixon, 2003 ; Perrot and Eyer, 2009 ; Didonna and Opal, 2019 ; Laura et al, 2019 ; Stone et al, 2021 ).…”