Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

Gan‐Or, Ziv; Dion, Patrick A.

doi:10.1080/15548627.2015.1067364

Cited by 232 publications

(234 citation statements)

References 212 publications

(257 reference statements)

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“…PD usually presents as a movement disorder, causing resting tremor, bradykinesia, stiffness, and poor balance but less commonly can also cause progressive dementia (Emre et al, 2007). Most PD cases are sporadic, but a number of genes are implicated in familial forms which point to failure of the autophagic-lysosomal system as a unifying concept in PD causation (Bras et al, 2014; Dehay et al, 2013; Gan-Or et al, 2015; Kalinderi et al, 2016). …”

Section: V-atpase –Related Lysosomal Acidification Failure In Diseasementioning

confidence: 99%

“…It is not known if α-syn affects the v-ATPase, but α-syn over-expression induces lysosomal de-acidification in vitro (Stefanis et al, 2001) and, in several mouse models, disrupts lysosomal function (Cuervo et al, 2004; Martinez-Vicente et al, 2008; Xilouri et al, 2009). Mutations of other genes which are causative for PD,, such as LRRK2, impair the autophagic-lysosomal system, including mitophagy (Gan-Or et al, 2015; Kalinderi et al, 2016; Su and Qi, 2013; Wang et al, 2012). The most common pathological mutation of LRRK2 (G2019S) causes a phenotype exhibiting lysosomal expansion and diminished lysosomal degradation of substrate.…”

Section: V-atpase –Related Lysosomal Acidification Failure In Diseasementioning

confidence: 99%

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Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Colacurcio

Nixon

2016

Ageing Research Reviews

398

329

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Autophagy and endocytosis deliver unneeded cellular materials to lysosomes for degradation. Beyond processing cellular waste, lysosomes release metabolites and ions that serve signaling and nutrient sensing roles, linking the functions of the lysosome to various pathways for intracellular metabolism and nutrient homeostasis. Each of these lysosomal behaviors is influenced by the intraluminal pH of the lysosome, which is maintained in the low acidic range by a proton pump, the vacuolar ATPase (v-ATPase). New reports implicate altered v-ATPase activity and lysosomal pH dysregulation in cellular aging, longevity, and adult-onset neurodegenerative diseases, including forms of Parkinson Disease and Alzheimer Disease. Genetic defects of subunits composing the v-ATPase or v-ATPase-related proteins occur in an increasingly recognized group of familial neurodegenerative diseases. Here, we review the expanding roles of the v-ATPase complex as a platform regulating lysosomal proteolysis and cellular homeostasis. We discuss the unique vulnerability of neurons to persistent low level lysosomal dysfunction and review recent clinical and experimental studies that link dysfunction of the v-ATPase complex to neurodegenerative diseases across the age spectrum.

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Section: V-atpase –Related Lysosomal Acidification Failure In Diseasementioning

confidence: 99%

Section: V-atpase –Related Lysosomal Acidification Failure In Diseasementioning

confidence: 99%

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Colacurcio

Nixon

2016

Ageing Research Reviews

398

329

View full text Add to dashboard Cite

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“…Large genetic studies have identified various risk factors for PD, including genome wide associated loci(Do, et al, 2011,International Parkinson Disease Genomics, et al, 2011,Nalls, et al, 2014,Satake, et al, 2009,Simon-Sanchez, et al, 2009) or mutations in specific genes such as GBA , LRRK2 , SNCA , VPS35 , SMPD1 , PARK2 , PINK1 , PARK7 and others (reviewed in (Gan-Or, et al, 2015,Trinh and Farrer, 2013)). However, none of these genetic loci or genes can currently explain the association between PD and melanoma.…”

Section: Introductionmentioning

confidence: 99%

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

Gan‐Or

Mohsin

Girard

et al. 2016

Neurobiology of Aging

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The MC1R gene, suggested to be involved in Parkinson disease (PD) and melanoma, was sequenced in PD patients (n=539) and controls (n=265) from New-York, and PD patients (n=551), rapid eye movement sleep behavior disorder (RBD) patients (n=351) and controls (n=956) of European ancestry. Sixty-eight MC1R variants were identified, including 7 common variants with frequency>0.01. None of the common variants was associated with PD or RBD in the different regression models. In a meta-analysis with fixed-effect model, the p.R160W variant was associated with an increased risk for PD (OR=1.22, 95%CI 1.02-1.47, p=0.03) but with significant heterogeneity (p=0.048). Removing one study that introduced the heterogeneity resulted in non-significant association (OR=1.11, 95%CI 0.92-1.35, p=0.27, heterogeneity p=0.57). Rare variants had similar frequencies in patients and controls (10.54% and 10.15%, respectively, p=0.75), and no cumulative effect of carrying more than one MC1R variant was found. The current study does not support a role for the MC1R p.R160W and other variants in susceptibility for PD or RBD.

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“…In the present study, we also observed an increase in Beclin-1 expression that paralleled the increases in LC3II, providing additional evidence of the induction of autophagy by HS exposure. Recent reports have shown that autophagy may play a defensive role in chronic neurodegenerative diseases such as Parkinson's disease [24], Alzheimer's disease [25], and Huntington's disease [26]. Moreover, previous studies have reported that HS-induced autophagy provided protection against neurodegeneration in the brain [9].…”

Section: Discussionmentioning

confidence: 99%

Heat Acclimation Regulates the Autophagy-Lysosome Function to Protect Against Heat Stroke-Induced Brain Injury in Mice

Yang

et al. 2017

Cell Physiol Biochem

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Background/Aims: The mechanisms underlying the protective role of heat acclimation (HA) in heat stroke (HS)-induced brain injury are still unclear. The autophagy-lysosome pathway is known to pay an important role in protecting stressed or diseased cells from death. Nevertheless, whether autophagy and lysosomes are involved in HA-mediated neuroprotection following HS exposure remains unclear. Methods: The protective effects of HA were assessed by rectal temperature, hematoxylin-eosin staining, transmission electron microscopic analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining, and Fluoro Jade B staining, after mice were subjected to HS. The effects of HA on autophagy and lysosomes were assessed in the presence of the autophagy inhibitor 3-methyladenine (3MA). Autophagy and lysosome-associated proteins were analysed by Western blotting. Results: We found that HA protected against HS-induced death and brain injury. HS can robustly induce autophagy and impair lysosome function. HA pre-conditioning significantly modulated the autophagy level, and improved lysosome function in HS mice. Furthermore, 3MA completely abolished the neuroprotective effect of HA on HS. Conclusion: HS may induce brain injury through lysosomal dysfunction and impaired autophagic flux. HA protected against HS-induced brain injury via a mechanism involving the autophagy-lysosome pathway.

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Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

Cited by 232 publications

References 212 publications

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

Heat Acclimation Regulates the Autophagy-Lysosome Function to Protect Against Heat Stroke-Induced Brain Injury in Mice

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