Publications
Taylor CA, Maor-Nof M, Metzl-Raz E, Hidalgo A, Yee C, Gitler AD, Shen K. bioRxiv [Preprint]. 2024
Histone deacetylase inhibition expands cellularproteostasis repertoires to enhance neuronal stress resilience
Neurons are long-lived, terminally differentiated cells with limited regenerative capacity. Cellular stressors such as endoplasmic reticulum (ER) protein folding stress and membrane trafficking stress accumulate as neurons age and accompany age-dependent neurodegeneration. Current strategies to improve neuronal resilience are focused on using factors to reprogram neurons or targeting specific proteostasis pathways. We discovered a different approach. In an unbiased screen for modifiers of neuronal membrane trafficking defects, we unexpectedly identified a role for histone deacetylases (HDACs) in limiting cellular flexibility in choosing cellular pathways to respond to diverse types of stress. Genetic or pharmacological inactivation of HDACs resulted in improved neuronal health in response to ER protein folding stress and endosomal membrane trafficking stress in C. elegans and mammalian neurons. Surprisingly, HDAC inhibition enabled neurons to activate latent proteostasis pathways tailored to the nature of the individual stress, instead of generalized transcriptional upregulation. These findings shape our understanding of neuronal stress responses and suggest new therapeutic strategies to enhance neuronal resilience.
Maor-Nof M, Shipony Z, Lopez-Gonzalez R, Nakayama L, Zhang YJ, Couthouis J, Blum JA, Castruita PA, Linares GR, Ruan K, Ramaswami G, Simon DJ, Nof A, Santana M, Han K, Sinnott-Armstrong N, Bassik MC, Geschwind DH, Tessier-Lavigne M, Attardi LD, Lloyd TE, Ichida JK, Gao FB, Greenleaf WJ, Yokoyama JS, Petrucelli L, Gitler AD. Cell. 2021
p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.
An optimized ATAC-seq protocol for genome-wide mapping of active regulatory elements in primary mouse cortical neurons
ATAC-seq is a versatile, adaptable, and widely adopted technique for mapping open chromatin regions. However, some biological systems, such as primary neurons, present unique challenges to its application. Conventional ATAC-seq would require the dissociation of the primary neurons after plating but dissociating them leads to rapid cell death and major changes in cell state, affecting ATAC-seq results. We have developed this modified ATAC-seq protocol to address this challenge for primary neurons, providing a high-quality and high-resolution accessible chromatin profile.
Maor-Nof M, Shipony Z, Marinov GK, Greenleaf WJ, Gitler AD.
STAR Protoc. 2021
Axonal Degeneration Is Regulated by a Transcriptional Program that Coordinates Expression of Pro- and Anti-degenerative Factors
ATAC-seq is a versatile, adaptable, and widely adopted technique for mapping open chromatin regions. However, some biological systems, such as primary neurons, present unique challenges to its application. Conventional ATAC-seq would require the dissociation of the primary neurons after plating but dissociating them leads to rapid cell death and major changes in cell state, affecting ATAC-seq results. We have developed this modified ATAC-seq protocol to address this challenge for primary neurons, providing a high-quality and high-resolution accessible chromatin profile.
Maor-Nof M, Romi E, Sar Shalom H, Ulisse V, Raanan C, Nof A, Leshkowitz D, Lang R, Yaron A. Neuron. 2016
Maor-Nof M, Homma N, Raanan C, Nof A, Hirokawa N,Yaron A. Cell Rep. 2013
Axonal pruning is actively regulated by the microtubule-destabilizing protein kinesin superfamily protein 2A
Extensive axonal pruning and neuronal cell death are critical events for the development of the nervous system. Like neuronal cell death, axonal elimination occurs in discrete steps; however, the regulators of these processes remain mostly elusive. Here, we identify the kinesin superfamily protein 2A (KIF2A) as a key executor of microtubule disassembly and axonal breakdown during axonal pruning. Knock-down of Kif2a, but not other microtubule depolymerization or severing proteins, protects axonal microtubules from disassembly upon trophic deprivation. We further confirmed and extended this result to demonstrate that the entire degeneration process is delayed in neurons from the Kif2a knockout mice. Finally, we show that the Kif2a-null mice exhibit normal sensory axon patterning early during development, but abnormal target hyperinnervation later on, as they compete for limited skin-derived trophic support. Overall, these findings reveal a central regulatory mechanism of axonal pruning during development.
Neurite pruning and neuronal cell death: spatial regulation of shared destruction programs
During development, neurons are initially overproduced and excess neurons are eliminated later on by programmed cell death. In a more refined developmental process termed pruning, excess axons and dendritic branches are removed while the cell body remains intact. In mature animals, axons that become disconnected as a result of injury are eliminated through a series of events collectively known as Wallerian degeneration. Recent evidence points to unexpected similarities between these three types of obliterative processes, as they share common regulators. These findings provide new ideas on how cellular destruction programs are spatially regulated in neurons.
Maor-Nof M, Yaron A.
Curr Opin Neurobiol. 2013