Endolysosomal dysfunction in Parkinson's disease: Recent developments and future challenges

Kett, Lauren R.; Dauer, William T.

doi:10.1002/mds.26797

Cited by 36 publications

(28 citation statements)

References 111 publications

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“…1). This complexity comes at a price: burdensome demands on the E-L system, which have been increasingly implicated in neurological diseases including PD (Kett and Dauer 2016;Wang et al 2018).…”

Section: Endolysosomal System In Neurons: Custom-made For Neuronal Fumentioning

confidence: 99%

Role of the endolysosomal system in Parkinson’s disease

Vidyadhara

Lee

Chandra

2019

Journal of Neurochemistry

116

105

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, affecting 1–1.5% of the total population. While progress has been made in understanding the neurodegenerative mechanisms that lead to cell death in late stages of PD, mechanisms for early, causal pathogenic events are still elusive. Recent developments in PD genetics increasingly point at endolysosomal (E‐L) system dysfunction as the early pathomechanism and key pathway affected in PD. Clathrin‐mediated synaptic endocytosis, an integral part of the neuronal E‐L system, is probably the main early target as evident in auxilin, RME‐8, and synaptojanin‐1 mutations that cause PD. Autophagy, another important pathway in the E‐L system, is crucial in maintaining proteostasis and a healthy mitochondrial pool, especially in neurons considering their inability to divide and requirement to function an entire life‐time. PINK1 and Parkin mutations severely perturb autophagy of dysfunctional mitochondria (mitophagy), both in the cell body and synaptic terminals of dopaminergic neurons, leading to PD. Endolysosomal sorting and trafficking is also crucial, which is complex in multi‐compartmentalized neurons. VPS35 and VPS13C mutations noted in PD target these mechanisms. Mutations in GBA comprise the most common risk factor for PD and initiate pathology by compromising lysosomal function. This is also the case for ATP13A2 mutations. Interestingly, α‐synuclein and LRRK2, key proteins involved in PD, function in different steps of the E‐L pathway and target their components to induce disease pathogenesis. In this review, we discuss these E‐L system genes that are linked to PD and how their dysfunction results in PD pathogenesis. This article is part of the Special Issue “Synuclein”.

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Section: Endolysosomal System In Neurons: Custom-made For Neuronal Fumentioning

confidence: 99%

Role of the endolysosomal system in Parkinson’s disease

Vidyadhara

Lee

Chandra

2019

Journal of Neurochemistry

116

105

View full text Add to dashboard Cite

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“…Studies suggest that endolysomal protein ATPase13A2 is involved in mitochondrial homeostasis, protein degradation pathways, and oxidative stress, potentially through the regulation of mono- and divalent cations, such as Zn2+ and H+ (Kett and Dauer, 2016). …”

Section: Atp13a2mentioning

confidence: 99%

“…Although the role of ATP13A2 has not been extensively characterized, studies have demonstrated that ATP13A2 colocalizes with structural lysosomal protein LAMP1/2a and lysotracker in homeostatic conditions, suggesting a role in lysosomal maintenance (Gusdon et al, 2012). A recent study found that ATP13A2 colocalizes with LC3, an autophagosome and late endosomal marker, perhaps specific to the multivesicular body (MVB) (Kett and Dauer, 2016). This suggests that ATP13A2 may be important in fusion of the autophagosome or vesicles from the MVB with the lysosome.…”

Section: Common Pathways In Pd Pathogenesismentioning

confidence: 99%

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Scott

Dawson

2017

Experimental Neurology

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Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Most PD cases are sporadic; however, rare familial forms have been identified. Autosomal recessive PD (ARPD) results from mutations in Parkin, PINK1, DJ-1, and ATP13A2, while rare, atypical juvenile ARPD result from mutations in FBXO7, DNAJC6, SYNJ1, and PLA2G6. Studying these genes and their function has revealed mitochondrial quality control, protein degradation processes, and oxidative stress responses as common pathways underlying PD pathogenesis. Understanding how aberrancy in these common processes leads to neurodegeneration has provided the field with numerous targets that may be therapeutically relevant to the development of disease-modifying treatments.

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“…Indeed, proteasome and lysosome inhibitors can delay Tau turnover and promote Tau-driven neuropathology (Zhang et al, 2005;Hamano et al, 2008). However, dysfunction of a third degradative pathway, the endolysosomal system, is also linked to AD and other neurodegenerative conditions that exhibit Tau accumulation, including Parkinson's disease (Rivero-Rios et al, 2015;Kett & Dauer, 2016;Small et al, 2017). Nevertheless, the role of the endolysosomal pathway in the clearance of Tau is almost completely unexplored.…”

Section: Introductionmentioning

confidence: 99%

Endolysosomal degradation of Tau and its role in glucocorticoid‐driven hippocampal malfunction

et al. 2018

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Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.

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Endolysosomal dysfunction in Parkinson's disease: Recent developments and future challenges

Cited by 36 publications

References 111 publications

Role of the endolysosomal system in Parkinson’s disease

Role of the endolysosomal system in Parkinson’s disease

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Endolysosomal degradation of Tau and its role in glucocorticoid‐driven hippocampal malfunction

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