Mutant HTT (huntingtin) impairs mitophagy in a cellular model of Huntington disease

Franco-Iborra, Sandra; Plaza-Zabala, Ainhoa; Montpeyó, Marta; Sebastián, David; Vila, Miquel; Martínez-Vicente, Marta

doi:10.1080/15548627.2020.1728096

Cited by 122 publications

(96 citation statements)

References 95 publications

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“…Indeed, microscopic examination of the dentate gyrus region revealed that basal mitophagy levels are diminished in a mouse model of HD compared to age-matched control animals (Sun et al, 2015 ). Supporting the neuroprotective role of mitophagy, genetic studies in flies and rodents uncovered that mHtt is associated directly with mitochondrial membranes and impairs mitochondrial integrity and mitophagy execution leading to neurodegeneration (Hwang et al, 2015 ; Khalil et al, 2015 ; Guo et al, 2016 ; Franco-Iborra et al, 2020 ).…”

Section: Neuroprotective Role Of Mitophagymentioning

confidence: 99%

Neuronal Mitophagy: Friend or Foe?

Doxaki

Palikaras

2021

Front. Cell Dev. Biol.

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Maintenance of neuronal homeostasis is a challenging task, due to unique cellular organization and bioenergetic demands of post-mitotic neurons. It is increasingly appreciated that impairment of mitochondrial homeostasis represents an early sign of neuronal dysfunction that is common in both age-related neurodegenerative as well as in neurodevelopmental disorders. Mitochondrial selective autophagy, known as mitophagy, regulates mitochondrial number ensuring cellular adaptation in response to several intracellular and environmental stimuli. Mounting evidence underlines that deregulation of mitophagy levels has an instructive role in the process of neurodegeneration. Although mitophagy induction mediates the elimination of damaged mitochondria and confers neuroprotection, uncontrolled runaway mitophagy could reduce mitochondrial content overstressing the remaining organelles and eventually triggering neuronal cell death. Unveiling the molecular mechanisms of neuronal mitophagy and its intricate role in neuronal survival and cell death, will assist in the development of novel mitophagy modulators to promote cellular and organismal homeostasis in health and disease.

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Section: Neuroprotective Role Of Mitophagymentioning

confidence: 99%

Neuronal Mitophagy: Friend or Foe?

Doxaki

Palikaras

2021

Front. Cell Dev. Biol.

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“…The normal HTT protein is extremely important for the development of neurons, but the gene responsible for HTT is sometimes mutated to express the mHTT with an aggregation tendency to damage the CNS [ 154 ]. Recent studies have shown that dopamine D2/D3 receptor activators could induce autophagy, thereby eliminating accumulated soluble mHTT.…”

Section: Autophagy and Nddsmentioning

confidence: 99%

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

Luo

Sandhu

Rungratanawanich

et al. 2020

IJMS

105

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With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its “double-edged sword”, autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.

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“…Htt is required for stress-induced selective autophagy, such as mitophagy and aggrephagy, as it facilitates cargo recognition and sequestration by interacting with the autophagy receptor p62 (Rui et al, 2015). Accordingly, the presence of empty autophagosomes and the accumulation of dysfunctional mitochondria has been reported in cellular and animal HD models (Martinez-Vicente et al, 2010;Franco-Iborra et al, 2020). Additionally, wtHtt interacts with the autophagy-activating kinase ULK1 and promotes its activation by interfering with the inhibitory binding of mTOR to ULK1 itself, thus regulating selective autophagy initiation (Rui et al, 2015).…”

Section: Huntington's Diseasementioning

confidence: 99%

Dysfunctional Autophagy and Endolysosomal System in Neurodegenerative Diseases: Relevance and Therapeutic Options

Giovedì

Ravanelli

Parisi

et al. 2020

Front. Cell. Neurosci.

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Autophagy and endolysosomal trafficking are crucial in neuronal development, function and survival. These processes ensure efficient removal of misfolded aggregation-prone proteins and damaged organelles, such as dysfunctional mitochondria, thus allowing the maintenance of proper cellular homeostasis. Beside this, emerging evidence has pointed to their involvement in the regulation of the synaptic proteome needed to guarantee an efficient neurotransmitter release and synaptic plasticity. Along this line, an intimate interplay between the molecular machinery regulating synaptic vesicle endocytosis and synaptic autophagy is emerging, suggesting that synaptic quality control mechanisms need to be tightly coupled to neurosecretion to secure release accuracy. Defects in autophagy and endolysosomal pathway have been associated with neuronal dysfunction and extensively reported in Alzheimer’s, Parkinson’s, Huntington’s and amyotrophic lateral sclerosis among other neurodegenerative diseases, with common features and emerging genetic bases. In this review, we focus on the multiple roles of autophagy and endolysosomal system in neuronal homeostasis and highlight how their defects probably contribute to synaptic default and neurodegeneration in the above-mentioned diseases, discussing the most recent options explored for therapeutic interventions.

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Mutant HTT (huntingtin) impairs mitophagy in a cellular model of Huntington disease

Cited by 122 publications

References 95 publications

Neuronal Mitophagy: Friend or Foe?

Neuronal Mitophagy: Friend or Foe?

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

Dysfunctional Autophagy and Endolysosomal System in Neurodegenerative Diseases: Relevance and Therapeutic Options

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