CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins.
Chen L, Liu Z, Zhou B, Wei C, Zhou Y, Rosenfeld MG, Fu XD, Chisholm AD, Jin Y
eLife. 2016 Jun 2;5. pii: e16072. doi: 10.7554/eLife.16072.


Axon injury triggers dramatic changes in gene expression. While transcriptional regulation of injury-induced gene expression is widely studied, less is known about the roles of RNA binding proteins (RBPs) in post-transcriptional regulation during axon regeneration. In C. elegans the CELF (CUGBP and Etr-3 Like Factor) family RBP UNC-75 is required for axon regeneration. Using crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq) we identify a set of genes involved in synaptic transmission as mRNA targets of UNC-75. In particular, we show that UNC-75 regulates alternative splicing of two mRNA isoforms of the SNARE Syntaxin/unc-64. In C. elegans mutants lacking unc-75 or its targets, regenerating axons form growth cones, yet are deficient in extension. Extending these findings to mammalian axon regeneration, we show that mouse Celf2 expression is upregulated after peripheral nerve injury and that Celf2 mutant mice are defective in axon regeneration. Further, mRNAs for several Syntaxins show CELF2 dependent regulation. Our data delineate a post-transcriptional regulatory pathway with a conserved role in regenerative axon extension.

Alzheimer’s disease: An acquired neurodegenerative laminopathy.
Frost B
Nucleus. 2016 May 3;7(3):275-83. doi: 10.1080/19491034.2016.1183859. Epub 2016 May 11.


The nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope. For most cell types, this depiction is accurate. In other cell types and in some pathological conditions, however, the smooth nuclear exterior is interrupted by tubular invaginations of the nuclear envelope, often referred to as a “nucleoplasmic reticulum,” into the deep nuclear interior. We have recently reported a significant expansion of the nucleoplasmic reticulum in postmortem human Alzheimer’s disease brain tissue. We found that dysfunction of the nucleoskeleton, a lamin-rich meshwork that coats the inner nuclear membrane and associated invaginations, is causal for Alzheimer’s disease-related neurodegeneration in vivo. Additionally, we demonstrated that proper function of the nucleoskeleton is required for survival of adult neurons and maintaining genomic architecture. Here, we elaborate on the significance of these findings in regard to pathological states and physiological aging, and discuss cellular causes and consequences of nuclear envelope invagination.

Vascular mTOR-dependent mechanisms linking the control of aging to Alzheimer’s disease.
Galvan V, Hart MJ
Biochimica et Biophysica Acta (BBA). 2016 May;1862(5):992-1007. doi: 10.1016/j.bbadis.2015.11.010. Epub 2015 Nov 27.


Aging is the strongest known risk factor for Alzheimer’s disease (AD). With the discovery of the mechanistic target of rapamycin (mTOR) as a critical pathway controlling the rate of aging in mice, molecules at the interface between the regulation of aging and the mechanisms of specific age-associated diseases can be identified. We will review emerging evidence that mTOR-dependent brain vascular dysfunction, a universal feature of aging, may be one of the mechanisms linking the regulation of the rate of aging to the pathogenesis of Alzheimer’s disease. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Lamin Dysfunction Mediates Neurodegeneration in Tauopathies.
Frost B, Bardai FH, Feany MB
Current Biology. 2016 Jan 11;26(1):129-36. doi: 10.1016/j.cub.2015.11.039. Epub 2015 Dec 24.


The filamentous meshwork formed by the lamin nucleoskeleton provides a scaffold for the anchoring of highly condensed heterochromatic DNA to the nuclear envelope, thereby establishing the three-dimensional architecture of the genome [1]. Insight into the importance of lamins to cellular viability can be gleaned from laminopathies, severe disorders caused by mutations in genes encoding lamins. A cellular consequence of lamin dysfunction in laminopathies is relaxation of heterochromatic DNA [1]. Similarly, we have recently reported the widespread relaxation of heterochromatin in tauopathies [1]: age-related progressive neurodegenerative disorders, including Alzheimer’s disease, that are pathologically characterized by aggregates of phosphorylated tau protein in the brain [2, 3]. Here we demonstrate that acquired lamin misregulation though aberrant cytoskeletal-nucleoskeletal coupling promotes relaxation of heterochromatin and neuronal death in an in vivo model of neurodegenerative tauopathy. Genetic manipulation of lamin function significantly modifies neurodegeneration in vivo, demonstrating that lamin pathology plays a causal role in tau-mediated neurotoxicity. We show that lamin dysfunction is conserved in human tauopathy, as super-resolution microscopy reveals a significantly disrupted nuclear lamina in postmortem tissue from human Alzheimer’s disease brain. Our study provides strong evidence that tauopathies are neurodegenerative laminopathies and identifies a new pathway mediating neuronal death in currently untreatable human neurodegenerative disorders, including Alzheimer’s disease.

Axon injury triggers EFA-6 mediated destabilization of axonal microtubules via TACC and doublecortin like kinase.
Chen L, Chuang M, Koorman T, Boxem M, Jin Y, Chisholm AD
eLife. 2015 Sep 4;4. doi: 10.7554/eLife.08695.


Axon injury triggers a series of changes in the axonal cytoskeleton that are prerequisites for effective axon regeneration. In Caenorhabditis elegans the signaling protein Exchange Factor for ARF-6 (EFA-6) is a potent intrinsic inhibitor of axon regrowth. Here we show that axon injury triggers rapid EFA-6-dependent inhibition of axonal microtubule (MT) dynamics, concomitant with relocalization of EFA-6. EFA-6 relocalization and axon regrowth inhibition require a conserved 18-aa motif in its otherwise intrinsically disordered N-terminal domain. The EFA-6 N-terminus binds the MT-associated proteins TAC-1/Transforming-Acidic-Coiled-Coil, and ZYG-8/Doublecortin-Like-Kinase, both of which are required for regenerative growth cone formation, and which act downstream of EFA-6. After injury TAC-1 and EFA-6 transiently relocalize to sites marked by the MT minus end binding protein PTRN-1/Patronin. We propose that EFA-6 acts as a bifunctional injury-responsive regulator of axonal MT dynamics, acting at the cell cortex in the steady state and at MT minus ends after injury.

Connecting the dots between tau dysfunction and neurodegeneration.
Frost B, Gotz J, Feany M
Trends in Cell Biology. 2015 Jan;25(1):46-53. doi: 10.1016/j.tcb.2014.07.005. Epub 2014 Aug 26.


Tauopathies are devastating and ultimately fatal neurodegenerative diseases, which are histopathologically defined by insoluble filamentous deposits of abnormally phosphorylated tau protein within neurons and glia. Identifying the causes of abnormal tau phosphorylation and subsequent aggregation has been the focus of much research, and is currently a major target for the development of therapeutic interventions for tauopathies, including Alzheimer’s disease (AD). Much has recently been learned about the sequence of events that lead from tau dysfunction to neuronal death. This review focuses on the cascade of events that are catalyzed by pathological tau, and highlights current and potential therapeutic strategies to target this pathway.

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