The Genetics of Monogenic Frontotemporal Dementia

Takada, Leonel Tadao

doi:10.1590/1980-57642015dn93000003

Cited by 46 publications

(31 citation statements)

References 101 publications

(240 reference statements)

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“…Approximately 10% of ALS cases are familial or hereditary. Of the various genetic causes of fALS, repeat expansions of the G 4 C 2 promoter of C9orf72 account for ∼40% of cases, while the same mutation accounts for 18% of familial FTD cases (Renton et al, 2014;Takada, 2015). The c9orf72 gene serves active physiological functions in a cell-specific manner.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2019

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with overlapping pathomechanisms, neurobehavioral features, and genetic etiologies. Individuals diagnosed with either disorder exhibit symptoms within a clinical spectrum. Symptoms of ALS involve neuromusculature deficits, reflecting upper and lower motor neurodegeneration, while the primary clinical features of FTD are behavioral and cognitive impairments, reflecting frontotemporal lobar degeneration. An intronic G 4 C 2 hexanucleotide repeat expansion (HRE) within the promoter region of chromosome 9 open reading frame 72 (C9orf72) is the predominant monogenic cause of both ALS and FTD. While the heightened risk to develop ALS/FTD in response to C9orf72 expansions is well-established, studies continue to define the precise mechanisms by which this mutation elicits neurodegeneration. Studies show that G 4 C 2 expansions undergo repeat-associated non-ATG dependent (RAN) translation, producing dipeptide repeat proteins (DRPs) with varying toxicities. Accumulation of DRPs in neurons, in particular arginine containing DRPs, have neurotoxic effects by potently impairing nucleocytoplasmic transport, nucleotide metabolism, lysosomal processes, and cellular metabolic pathways. How these pathophysiological effects of C9orf72 expansions engage and elicit immune activity with additional neurobiological consequences is an important line of future investigations. Immunoreactive microglia and elevated levels of peripheral inflammatory cytokines noted in individuals with C9orf72 ALS/FTD provide evidence that persistent immune activation has a causative role in the progression of each disorder. This review highlights the current understanding of the cellular, proteomic and genetic substrates through which G 4 C 2 HREs may elicit detrimental immune activity, facilitating region-specific neurodegeneration in C9orf72 mediated ALS/FTD. We in particular emphasize interactions between intracellular pathways induced by C9orf72 expansions and innate immune inflammasome complexes, intracellular receptors responsible for eliciting inflammation in response to cellular

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Section: Introductionmentioning

confidence: 99%

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2019

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“…Genetic mutations of tau can cause familial tauopathies, which are commonly found in frontal temporal dementia (FTD), including a range of clinical conditions like Pick's disease, corticobasal dementia, and progressive supranuclear palsy [63,64]. Mutations of tau were first discovered in the late 1990s in inherited FTD families [65], and it was the first known monogenic mutations that could cause FTD [63,64]. Epidemiological surveys showed MAPT mutations are responsible for 5-20% FTD cases [63].…”

Section: Tau Mutations In Neurodegenerative Disordersmentioning

confidence: 99%

Tauopathy

Ran¹,

Sang²,

Chang³

2019

Cognitive Disorders

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Tauopathy is a category of neurodegenerative diseases that are caused or associated with pathological tau protein. Some of the diseases are relatively common, which include Alzheimer's disease (AD) and various Parkinsonism (PD). Tau protein is a type of microtubule-associated protein (MAP), encoded by the gene MAPT (microtubule-associated protein tau). Normally, tau binds to microtubule, supporting the assembling and structure of cytoskeletons. However, in tauopathy, normal tau protein undergoes abnormal posttranslational modifications and detaches from microtubule; furthermore, they may aggregate forming paired helical filaments (PHF) or straight filaments (SF). Abundant PHF could be observed under microscope as fibrillary tangles. In this chapter, we will introduce the pathogenesis process of tauopathy with regard to the posttranslational modifications of the protein, the animal models, and the developing treatments against tauopathy from a clinical prospective.

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“…Clinical similarities between BD and bv-FTD have been a focus of research in the past decade (Dols et al, 2016;Kerstein et al, 2013;Lopes and Fernandes, 2012;Masouy et al, 2011;Rubino et al, 2017;Woolley et al, 2011;Woolley et al, 2007), raising the question whether the same molecular pathways might explain shared clinical symptoms. The presence of different misfolded proteins in the brain, as well as genetic mutations (associated with these misfolded proteins or otherwise), are hallmarks in the pathology of FTD (Lowe, 2011;Mackenzie and Neumann, 2016;Takada, 2015Takada, , 2017. In addition, other molecular pathways, such as inflammation, neuroprotection and oxidative stress, have been further investigated in BD (Muneer, 2016).…”

Section: Introductionmentioning

confidence: 99%

A review on shared clinical and biological aspects of bipolar disorder and frontotemporal dementia

Nascimento¹,

Villela²,

Rodriguez³

et al. 2018

Preprint

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Mental disorders are highly prevalent and important causes of medical burden worldwide. Co-occurrence of neurological and psychiatric symptoms are observed among mental disorders, representing a challenge for their differential diagnosis. Psychiatrists and neurologists have faced challenges in diagnosing older adults presenting behavioral changes. This is the case for early frontotemporal dementia (FTD) and late bipolar disorder. Early FTD is characterized by behavioral or language disturbances in the absence of cognitive symptoms. Consequently, patients with the behavioral subtype of FTD (bv-FTD) can be initially misdiagnosed as having a psychiatric disorder, typically depression or bipolar disorder (BD). Bipolar disorder is associated with a higher risk of dementia in older adults and cognitive impairment, where a subset of patients presents a neuroprogressive pattern during the disease course. Clinical similarities between BD and bv-FTD raise the question whether common molecular pathways might explain shared clinical symptoms. In fact, studies have also shown presence of molecular signatures related to bv-FTD in BD patients. Here, we reviewed existing data on clinical and molecular similarities between BD and FTD and propose biological pathways to be further investigated as common or specific markers of BD and FTD.

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The Genetics of Monogenic Frontotemporal Dementia

Cited by 46 publications

References 101 publications

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Tauopathy

A review on shared clinical and biological aspects of bipolar disorder and frontotemporal dementia

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