Autophagy in neurodegenerative diseases: From pathogenic dysfunction to therapeutic modulation

Martínez-Vicente, Marta

doi:10.1016/j.semcdb.2015.03.005

Cited by 99 publications

(56 citation statements)

References 184 publications

(183 reference statements)

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“…In [15] . Similarly, in ALS, TDP43 aggregates have been identifi ed in almost all sporadic and genetic cases [9,10,[15][16][17][18][19][20] . Although it is still not conclusive that these cytoplasmic inclusions themselves are toxic or merely serve to precipitate toxic cellular components and minimize their detrimental consequences, accumulating evidence reveals that the perturbation of autophagy primarily contributes to their existence and the pathogenesis of these diseases [21] .…”

Section: Defective Autophagy May Be a Central Player In Mn Diseases Amentioning

confidence: 93%

“…Autophagy, an intracellular degradation pathway for the clearance of damaged organelles and aggregation-prone proteins by lysosomes, is essential for the maintenance of protein homeostasis [9,10] . Generally, there are three distinctive types: macroautophagy, microautophagy, and cheparone-mediated autophagy.…”

Section: Defective Autophagy May Be a Central Player In Mn Diseases Amentioning

confidence: 99%

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Dysfunction of autophagy as the pathological mechanism of motor neuron disease based on a patient-specific disease model

et al. 2015

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Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteostasis and the accumulation of toxic proteins in neurons, is a central player in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). The clinical pathology of ALS is complex and many genes associated with autophagy and RNA processing are mutated in patients with the familial form. But a causal relationship between autophagic dysfunction and ALS has not been fully established. More importantly, studies on the pathological mechanism of ALS are mainly based on animal models that may not precisely recapitulate the disease itself in human beings. The development of human iPSC techniques allows us to address these issues directly in human cell models that may profoundly influence drug discovery for ALS.

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Section: Defective Autophagy May Be a Central Player In Mn Diseases Amentioning

confidence: 93%

Section: Defective Autophagy May Be a Central Player In Mn Diseases Amentioning

confidence: 99%

Dysfunction of autophagy as the pathological mechanism of motor neuron disease based on a patient-specific disease model

et al. 2015

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“…This is the basis for the role of autophagy in several neurologic diseases (Ghavami et al, 2014). Particularly in age-related diseases, both macroautophagy and chaperonemediated autophagy become less efficient with time, contributing to the gradual decline in cognitive performance (Martinez-Vicente, 2015). Additionally, alterations in proteins that target mitochondria to autophagic degradation, ] c can be induced through the increase of ion entry from the extracellular environment or through the release of Ca 2+ from the ER.…”

Section: Autophagy Ca 21 and The Central Nervous Systemmentioning

confidence: 99%

Modulation of Autophagy by Calcium Signalosome in Human Disease

et al. 2016

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Autophagy is a catabolic process that is largely regulated by extracellular and intracellular signaling pathways that are central to cellular metabolism and growth. Mounting evidence has shown that ion channels and transporters are important for basal autophagy functioning and influence autophagy to handle stressful situations. Besides its role in cell proliferation and apoptosis, intracellular Ca 21 is widely recognized as a key regulator of autophagy, acting through the modulation of pathways such as the mechanistic target of rapamycin complex 1, calcium/calmodulin-dependent protein kinase kinase 2, and protein kinase C. Proper spatiotemporal Ca 21 availability, coupled with a controlled ionic flow among the extracellular milieu, storage compartments, and the cytosol, is critical in determining the role played by Ca 21 on autophagy and on cell fate. The crosstalk between Ca 21 and autophagy has a central role in cellular homeostasis and survival during several physiologic and pathologic conditions. Here we review the main findings concerning the mechanisms and roles of Ca 21 -modulated autophagy, focusing on human disorders ranging from cancer to neurologic diseases and immunity. By identifying mechanisms, players, and pathways that either induce or suppress autophagy, new promising approaches for preventing and treating human disorders emerge, including those based on the modulation of Ca 21 -mediated autophagy.

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“…In the CNS, neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and acute CNS diseases, are all associated with the alteration of autophagy, resulting in the loss of neurons [12,13]. In chronic conditions, loss of autophagy is considered to the reason for neurodegeneration, but in acute nervous system disease, it is considered to contribute toward the injury of neurons [12,14].…”

Section: Introductionmentioning

confidence: 99%

Detection of autophagy in Hirschsprung’s disease

Huang¹,

Ge²,

Li³

et al. 2015

NeuroReport

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Hirschsprung's disease (HD) is a common congenital gastrointestinal malformation, characterized by the lack of ganglion cells from the distal rectum to the proximal bowel, but the pathogenesis is not well understood. This paper evaluates the effects of autophagy in HD. Using electron microscopy, the autophagosomes were detected in three segments: narrow segment (NS), transitional segment (TS), and dilated segment (DS). Typical autophagosome structures are found in the Auerbach plexus of both NS and TS. Real-time PCR results showed that Beclin1 (NS vs. TS, P<0.01) and LC3 (NS vs. TS, P<0.05) mRNA were the highest in the NS, but p75 (NS vs. TS, P<0.01) was the highest in the DS. Correlation analysis results showed a positive correlation between Beclin1 and LC3 mRNA levels (R=0.736, P=0.000), whereas inverse correlations were found between p75 and Beclin1/LC3 mRNA levels (p75 vs. Beclin1: R=-0.714, P=0.000; p75 vs. LC3: R=-0.619, P=0.000). Immunohistochemistry analyses indicated a consistent result with mRNA levels, by increased Beclin1-positive and LC3-positive neurons, but reduced p75-positive neurons in the Auerbach plexus of TS compared with DS. These findings indicated that autophagy exists in the bowel of patients with HD. On the basis of the detection of the highest expression of the autophagy genes in NS, autophagy may additionally cause the lack of neurons.

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Autophagy in neurodegenerative diseases: From pathogenic dysfunction to therapeutic modulation

Cited by 99 publications

References 184 publications

Dysfunction of autophagy as the pathological mechanism of motor neuron disease based on a patient-specific disease model

Dysfunction of autophagy as the pathological mechanism of motor neuron disease based on a patient-specific disease model

Modulation of Autophagy by Calcium Signalosome in Human Disease

Detection of autophagy in Hirschsprung’s disease

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