Mitochondria Dysfunction in Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: Lessons From Drosophila Models

Anoar, Sharifah; Woodling, Nathaniel S.; Niccoli, Teresa

doi:10.3389/fnins.2021.786076

Cited by 22 publications

(14 citation statements)

References 286 publications

(293 reference statements)

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Section: Introductionmentioning

confidence: 99%

“…To date, there are at least 17 common genes that have been linked to the susceptibility of familial forms of ALS and FTD ( Table 1 ) (Al-Saif et al, 2011 ; Belzil et al, 2013 ; Liscic et al, 2020 ; Anoar et al, 2021 ). Hexanucleotide repeat expansions within C9ORF72 , mutations in TARDBP ( or TDP-43 ) and FUS represent the majority of autosomal dominant mutations in familial ALS (Liscic et al, 2020 ; Anoar et al, 2021 ). Whereas C9ORF72 , progranulin ( GRN) , and microtubule-associated protein tau ( MAPT) represent the majority of autosomal dominant mutations found in familial FTD (Liscic et al, 2020 ; Anoar et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Hexanucleotide repeat expansions within C9ORF72 , mutations in TARDBP ( or TDP-43 ) and FUS represent the majority of autosomal dominant mutations in familial ALS (Liscic et al, 2020 ; Anoar et al, 2021 ). Whereas C9ORF72 , progranulin ( GRN) , and microtubule-associated protein tau ( MAPT) represent the majority of autosomal dominant mutations found in familial FTD (Liscic et al, 2020 ; Anoar et al, 2021 ). Based on the most frequent overlapping genes and pathological protein deposits of ALS and FTLD, these diseases can be further classified as being ALS-TDP, ALS-FUS, ALS-C9 or FTLD-TDP, FTLD-FUS, FTLD-C9.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

Gelon

Dutchak

Sephton

2022

Front. Mol. Neurosci.

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Synaptic loss is a pathological feature of all neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is a disease of the cortical and spinal motor neurons resulting in fatal paralysis due to denervation of muscles. FTD is a form of dementia that primarily affects brain regions controlling cognition, language and behavior. Once classified as two distinct diseases, ALS and FTD are now considered as part of a common disease spectrum based on overlapping clinical, pathological and genetic evidence. At the cellular level, aggregation of common proteins and overlapping gene susceptibilities are shared in both ALS and FTD. Despite the convergence of these two fields of research, the underlying disease mechanisms remain elusive. However, recent discovers from ALS and FTD patient studies and models of ALS/FTD strongly suggests that synaptic dysfunction is an early event in the disease process and a unifying hallmark of these diseases. This review provides a summary of the reported anatomical and cellular changes that occur in cortical and spinal motor neurons in ALS and FTD tissues and models of disease. We also highlight studies that identify changes in the proteome and transcriptome of ALS and FTD models and provide a conceptual overview of the processes that contribute to synaptic dysfunction in these diseases. Due to space limitations and the vast number of publications in the ALS and FTD fields, many articles have not been discussed in this review. As such, this review focuses on the three most common shared mutations in ALS and FTD, the hexanucleuotide repeat expansion within intron 1 of chromosome 9 open reading frame 72 (C9ORF72), transactive response DNA binding protein 43 (TARDBP or TDP-43) and fused in sarcoma (FUS), with the intention of highlighting common pathways that promote synaptic dysfunction in the ALS-FTD disease spectrum.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

Gelon

Dutchak

Sephton

2022

Front. Mol. Neurosci.

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“…FTD is the second most common form of dementia in individuals younger than 65 years [ 343 ], and ALS and FTD are thought to form opposite ends of the same disease spectrum [ 344 ]. Several mechanisms are implicated in the pathophysiology of FTD, including ER stress [ 345 ], mitochondrial dysfunction [ 346 ], oxidative stress [ 347 ], disruption in intracellular trafficking [ 275 ], proteostasis disruption [ 320 ], excitotoxicity [ 348 ], DNA damage [ 347 ], and abnormal RNA homeostasis [ 320 ]. ALS and FTD also have significant pathological and genetic overlap [ 349 ].…”

Section: Mechanisms Of Cell Death Induced By Dna Damage In Neurodegen...mentioning

confidence: 99%

The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

Shadfar

Brocardo

Atkin

2022

IJMS

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Human cells are exposed to numerous exogenous and endogenous insults every day. Unlike other molecules, DNA cannot be replaced by resynthesis, hence damage to DNA can have major consequences for the cell. The DNA damage response contains overlapping signalling networks that repair DNA and hence maintain genomic integrity, and aberrant DNA damage responses are increasingly described in neurodegenerative diseases. Furthermore, DNA repair declines during aging, which is the biggest risk factor for these conditions. If unrepaired, the accumulation of DNA damage results in death to eliminate cells with defective genomes. This is particularly important for postmitotic neurons because they have a limited capacity to proliferate, thus they must be maintained for life. Neuronal death is thus an important process in neurodegenerative disorders. In addition, the inability of neurons to divide renders them susceptible to senescence or re-entry to the cell cycle. The field of cell death has expanded significantly in recent years, and many new mechanisms have been described in various cell types, including neurons. Several of these mechanisms are linked to DNA damage. In this review, we provide an overview of the cell death pathways induced by DNA damage that are relevant to neurons and discuss the possible involvement of these mechanisms in neurodegenerative conditions.

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“…In HD, despite its cause is purely genetic, the interactions of the mutated huntingtin protein with mitochondria is one of the earliest events in the development of the disease, and cause mitophagy, synaptic degeneration, defective mitochondrial transport, excessive mitochondrial fragmentation and failure to remove dead mitochondria [reviewed in Sawant et al (2021)]. In ALS and FTD, the impairment of mitochondrial function has been widely studied, and many genes are involved in mitochondrial stress, dynamics, structure, bioenergetics and calcium buffering [reviewed in Smith et al (2019) and Anoar et al (2021)]. One of the major regulators of mitochondrial homeostasis is the prohibitin (PHB) complex (Lin and Beal, 2006;Artal-Sanz and Tavernarakis, 2009a).…”

Section: Introductionmentioning

confidence: 99%

Prohibitins in neurodegeneration and mitochondrial homeostasis

Fernandez-Abascal

Artal‐Sanz

2022

Front. Aging

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The incidence of age-related neurodegenerative disorders has risen with the increase of life expectancy. Unfortunately, the diagnosis of such disorders is in most cases only possible when the neurodegeneration status is already advanced, and symptoms are evident. Although age-related neurodegeneration is a common phenomenon in living animals, the cellular and molecular mechanisms behind remain poorly understood. Pathways leading to neurodegeneration usually diverge from a common starting point, mitochondrial stress, which can serve as a potential target for early diagnosis and treatments. Interestingly, the evolutionarily conserved mitochondrial prohibitin (PHB) complex is a key regulator of ageing and metabolism that has been associated with neurodegenerative diseases. However, its role in neurodegeneration is still not well characterized. The PHB complex shows protective or toxic effects in different genetic and physiological contexts, while mitochondrial and cellular stress promote both up and downregulation of PHB expression. With this review we aim to shed light into the complex world of PHB’s function in neurodegeneration by putting together the latest advances in neurodegeneration and mitochondrial homeostasis associated with PHB. A better understanding of the role of PHB in neurodegeneration will add knowledge to neuron deterioration during ageing and help to identify early molecular markers of mitochondrial stress. This review will deepen our understanding of age-related neurodegeneration and provide questions to be addressed, relevant to human health and to improve the life quality of the elderly.

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Mitochondria Dysfunction in Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: Lessons From Drosophila Models

Cited by 22 publications

References 286 publications

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

Prohibitins in neurodegeneration and mitochondrial homeostasis

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