Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy

Chornenkyy, Yevgen; Fardo, David W.; Nelson, Peter T.

doi:10.1038/s41374-019-0196-y

Cited by 70 publications

(48 citation statements)

References 197 publications

(185 reference statements)

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“…An interesting finding is that 28% of the variants were identified in CMT2/dSMA genes. These data confirm the emerging genetic pleiotropy of ALS [1,2,9,58]. More specifically, in relation to the specific design of our panel, our data suggest an overlap with other diseases sharing degeneration of motor axons and neurons as a common feature, such as the axonal hereditary neuropathies [9].…”

Section: Discussionsupporting

confidence: 84%

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

Scarlino¹,

Domi²,

Pozzi³

et al. 2020

IJMS

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Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of ALS using targeted next generation sequencing (NGS) analysis, enriched in motor neuron diseases (MND)-associated genes which are also implicated in axonal hereditary motor neuropathy (HMN), in order to investigate if disease expression, including the progression rate, could be influenced by the combination of multiple rare gene variants. We analyzed 29 genes in an Italian cohort of 83 patients with both familial and sporadic ALS. Overall, we detected 43 rare variants in 17 different genes and found that 43.4% of the ALS patients harbored a variant in at least one of the investigated genes. Of note, 27.9% of the variants were identified in other MND- and HMN-associated genes. Moreover, multiple gene variants were identified in 17% of the patients. The burden of rare variants is associated with reduced survival and with the time to reach King stage 4, i.e., the time to reach the need for percutaneous endoscopic gastrostomy (PEG) positioning or non-invasive mechanical ventilation (NIMV) initiation, independently of known negative prognostic factors. Our data contribute to a better understanding of the molecular basis of ALS supporting the hypothesis that rare variant burden could play a role in the multistep model of disease and could exert a negative prognostic effect. Moreover, we further extend the genetic landscape of ALS to other MND-associated genes traditionally implicated in degenerative diseases of peripheral axons, such as HMN and CMT2.

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Section: Discussionsupporting

confidence: 84%

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

Scarlino¹,

Domi²,

Pozzi³

et al. 2020

IJMS

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“…Specifically, a better understanding of TDP-43 localization regulators will surely shed light on novel therapeutics that have the potential to be more effective earlier in disease, more generalizable to most ALS cases, and more informative biomarkers for diagnosis and analysis of progression for ALS. Lastly, given that TDP-43 pathology can also coexist with other aggregate-prone proteins, such as C9ORF72 DPRs, Tau, α-Synuclein, and poly-Q expanded Huntingtin, insight into the role of TDP-43 mislocalization in its pathogenic function will serve to better understand pathology and modes of degeneration across a spectrum of neurodegenerative diseases [184,[285][286][287][288].…”

Section: Resultsmentioning

confidence: 99%

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Suk

Rousseaux

2020

Mol Neurodegeneration

257

170

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Since its discovery as a primary component in cytoplasmic aggregates in post-mortem tissue of patients with Amyotrophic Lateral Sclerosis (ALS), TAR DNA Binding Protein 43 kDa (TDP-43) has remained a central focus to understand the disease. TDP-43 links both familial and sporadic forms of ALS as mutations are causative for disease and cytoplasmic aggregates are a hallmark of nearly all cases, regardless of TDP-43 mutational status. Research has focused on the formation and consequences of cytosolic protein aggregates as drivers of ALS pathology through both gainand loss-of-function mechanisms. Not only does aggregation sequester the normal function of TDP-43, but these aggregates also actively block normal cellular processes inevitably leading to cellular demise in a short time span. Although there may be some benefit to therapeutically targeting TDP-43 aggregation, this step may be too late in disease development to have substantial therapeutic benefit. However, TDP-43 pathology appears to be tightly linked with its mislocalization from the nucleus to the cytoplasm, making it difficult to decouple the consequences of nuclearto-cytoplasmic mislocalization from protein aggregation. Studies focusing on the effects of TDP-43 mislocalization have demonstrated both gain-and loss-of-function consequences including altered splicing regulation, over responsiveness to cellular stressors, increases in DNA damage, and transcriptome-wide changes. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 thus suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. In this review, we bring forth the theme of protein mislocalization as a key mechanism underlying ALS, by highlighting the importance of maintaining subcellular proteostasis along with the gain-and loss-of-functional consequences when TDP-43 localization is dysregulated. Additional research, focusing on early events in TDP-43 pathogenesis (i.e. to the protein mislocalization stage) will provide insight into disease mechanisms, therapeutic targets, and novel biomarkers for ALS.

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“…Regardless of the indication, there are several requirements in successfully identifying new treatments. [6][7][8]. Furthermore, the brain is a protected organ, and accordingly, entry of small molecule therapeutics into the CNS can be limited [9].…”

Section: Introductionmentioning

confidence: 99%

Drugging DNA Damage Repair Pathways for Trinucleotide Repeat Expansion Diseases

Benn¹,

Gibson²,

Reynolds³

2021

JHD

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DNA damage repair (DDR) mechanisms have been implicated in a number of neurodegenerative diseases (both genetically determined and sporadic). Consistent with this, recent genome-wide association studies in Huntington’s disease (HD) and other trinucleotide repeat expansion diseases have highlighted genes involved in DDR mechanisms as modifiers for age of onset, rate of progression and somatic instability. At least some clinical genetic modifiers have been shown to have a role in modulating trinucleotide repeat expansion biology and could therefore provide new disease-modifying therapeutic targets. In this review, we focus on key considerations with respect to drug discovery and development using DDR mechanisms as a target for trinucleotide repeat expansion diseases. Six areas are covered with specific reference to DDR and HD: 1) Target identification and validation; 2) Candidate selection including therapeutic modality and delivery; 3) Target drug exposure with particular focus on blood-brain barrier penetration, engagement and expression of pharmacology; 4) Safety; 5) Preclinical models as predictors of therapeutic efficacy; 6) Clinical outcome measures including biomarkers.

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Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy

Cited by 70 publications

References 197 publications

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Drugging DNA Damage Repair Pathways for Trinucleotide Repeat Expansion Diseases

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