Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Riku, Yuichi; Seilhean, Danielle; Duyckaerts, Charles; Boluda, Susana; Iguchi, Yohei; Ishigaki, Shinsuke; Iwasaki, Yasushi; Yoshida, Mari; Sobue, Gen; Katsuno, Masahisa

doi:10.3390/ijms22083843

Cited by 18 publications

(15 citation statements)

References 120 publications

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“…TAR DNA-binding protein 43 (TDP-43) is the major protein that accumulates in ALS. Specifically, the accumulation of its C-terminal fragments appears to track the disease phenotype [ 89 ]. To better understand various mechanisms of pathogenesis, multiple groups have successfully employed CRISPR-Cas9 genome editing, paired with specific donor DNA, to introduce human mutations into the endogenous mouse gene encoding TDP-43 [ 90 , 91 ].…”

Section: Crispr-cas9 In Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders

Plano

Calabrese

Conoci

et al. 2022

IJMS

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Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease represent some of the most prevalent neurodegenerative disorders afflicting millions of people worldwide. Unfortunately, there is a lack of efficacious treatments to cure or stop the progression of these disorders. While the causes of such a lack of therapies can be attributed to various reasons, the disappointing results of recent clinical trials suggest the need for novel and innovative approaches. Since its discovery, there has been a growing excitement around the potential for CRISPR-Cas9 mediated gene editing to identify novel mechanistic insights into disease pathogenesis and to mediate accurate gene therapy. To this end, the literature is rich with experiments aimed at generating novel models of these disorders and offering proof-of-concept studies in preclinical animal models validating the great potential and versatility of this gene-editing system. In this review, we provide an overview of how the CRISPR-Cas9 systems have been used in these neurodegenerative disorders.

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Section: Crispr-cas9 In Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders

Plano

Calabrese

Conoci

et al. 2022

IJMS

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“…Overall, it is striking that, already in the first four decades of the twentieth century, the notion of a progressively spreading pathology beyond the motor cortex had been acknowledged as being the biological basis of neuropsychological changes in ALS [ 9 , 48 ]—somehow anticipating current theories of sequential, corticofugal stages underlying both motor and cognitive/behavioral involvement within the ALS-FTD spectrum [ 93 ].…”

Section: Histopathological Recordsmentioning

confidence: 99%

Cognitive and behavioral involvement in ALS has been known for more than a century

Zago

Lorusso²,

Aiello

et al. 2022

Neurol Sci

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Background Among clinicians and researchers, it is common knowledge that, in ALS, cognitive and behavioral involvement within the spectrum of frontotemporal degenerations (FTDs) begun to be regarded as a fact in the late 1990s of the twentieth century. By contrast, a considerable body of evidence on cognitive/behavioral changes in ALS can be traced in the literature dating from the late nineteenth century. Methods Worldwide reports on cognitive/behavioral involvement in ALS dating from 1886 to 1981 were retrieved thanks to Biblioteca di Area Medica “Adolfo Ferrate,” Sistema Bibliotecario di Ateneo, University of Pavia, Pavia, Italy and qualitatively synthetized. Results One-hundred and seventy-four cases of ALS with co-occurring FTD-like cognitive/behavioral changes, described in Europe, America, and Asia, were detected. Neuropsychological phenotypes were consistent with the revised Strong et al.’s consensus criteria. Clinical observations were not infrequently supported by histopathological, post-mortem verifications of extra-motor, cortical/sub-cortical alterations, as well as by in vivo instrumental exams—i.e., assessments of brain morphology/physiology and psychometric testing. In this regard, as earlier as 1907, the notion of motor and cognitive/behavioral features in ALS yielding from the same underlying pathology was acknowledged. Hereditary occurrences of ALS with cognitive/behavioral dysfunctions were reported, as well as familial associations with ALS-unrelated brain disorders. Neuropsychological symptoms often occurred before motor ones. Bulbar involvement was at times acknowledged as a risk factor for cognitive/behavioral changes in ALS. Discussion Historical observations herewith delivered can be regarded as the antecedents of current knowledge on cognitive/behavioral impairment in the ALS-FTD spectrum.

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“…TDP-43 has been shown to play a crucial role in multiple cellular homeostasis, including the regulation of mRNAs involved in neuronal development [ 16 , 17 ]. Although TDP-43 is strongly implicated in the pathogenesis of ALS and FTLD-TDP [ 18 ], the mechanism by which TDP-43 dysfunction or aggregation occurs and causes neurodegeneration remains unknown. It should be noted that TDP-43 proteinopathy is mediated by both the loss-of-function and the gain-of-toxic-function of TDP-43 proteins in complicated manners [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Dissection of TDP-43 as a Leading Cause of ALS/FTLD

Tamaki

Urushitani

2022

IJMS

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TAR DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in pivotal cellular functions, especially in RNA metabolism. Hyperphosphorylated and ubiquitinated TDP-43-positive neuronal cytoplasmic inclusions are identified in the brain and spinal cord in most cases of amyotrophic lateral sclerosis (ALS) and a substantial proportion of frontotemporal lobar degeneration (FTLD) cases. TDP-43 dysfunctions and cytoplasmic aggregation seem to be the central pathogenicity in ALS and FTLD. Therefore, unraveling both the physiological and pathological mechanisms of TDP-43 may enable the exploration of novel therapeutic strategies. This review highlights the current understanding of TDP-43 biology and pathology, describing the cellular processes involved in the pathogeneses of ALS and FTLD, such as post-translational modifications, RNA metabolism, liquid–liquid phase separation, proteolysis, and the potential prion-like propagation propensity of the TDP-43 inclusions.

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Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Cited by 18 publications

References 120 publications

Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders

Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders

Cognitive and behavioral involvement in ALS has been known for more than a century

Molecular Dissection of TDP-43 as a Leading Cause of ALS/FTLD

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