TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling

Abstract

SUMMARY Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43 mediated impairments are conserved in mammalian cells, and importantly the human orthologue CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to ALS/FTD.

CRISPR–Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity

“…Genetic screens in simple experimental model organisms like yeast, flies, and worms have empowered the discovery of fundamental biological processes including mechanisms of human disease 23 . For example, we and others have used genetic screens in model systems to identify modifiers of toxicity elicited by aggregation-prone neurodegenerative disease proteins, such as TDP-43, FUS, Amyloid-β, alpha-synuclein, mutant huntingtin, and C9orf72 DPRs 15 , 16 , 24 – 34 . Underscoring the impact of these simple model systems, some of the modifier genes from the genetic screens have been validated in mouse models and even connected to human disease through genetics and neuropathology 35 – 37 .…”

Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity

“…Upon heat stress, SEC is recruited to major heat shock loci on the polytene chromosomes and, further, has been shown to regulate the expression of a major heat shock protein Hsp70 17 . Dysfunction of the heat shock response, which helps maintain proteostasis, is associated with TDP-43 toxicity 33 – 35 . We therefore probed whether TDP-43 colocalized to these targets of SEC.…”

Role ofCNC1gene in TDP-43 aggregation-induced oxidative stress-mediated cell death inS. cerevisiaemodel of ALS

“…Overall, several molecular mechanisms have been proposed for causing the TDP-43 proteinopathy such as impaired endocytosis, increased localization of TDP-43 to the mitochondria, dysregulation of the ubiquitin proteasomemediated protein degradation, prion-like behaviour of TDP-43, disturbances in the chromatin remodelling and oxidative stress etc. [2,11,[16][17][18][19][20][21][22]87]. Of note, TDP-43 has also been shown to aberrantly localize to the mitochondria and affect the mitochondrial translation [19].…”

“…In fact, this abnormal mis-localization and aggregation of TDP-43 in the cytoplasm has also been demonstrated to lead to impaired endocytosis, increased aberrant localization of TDP-43 to the mitochondria, dysregulation of the ubiquitin proteasome-mediated protein degradation, dysfunctional metal ion homeostasis, disturbances in the chromatin remodelling and oxidative stress etc. [2,11,[16][17][18][19][20][21][22]. Additionally, several abnormal post-translational modifications such as cysteine oxidation, acetylation, ubiquitination, hyper-phosphorylation and PARylation have also been proposed to contribute to the TDP-43 toxicity [2,23].…”