Endo‐lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?

Whyte, Lauren S.; Lau, Adeline A.; Hemsley, Kim M.; Hopwood, John J.; Sargeant, Timothy J.

doi:10.1111/jnc.13935

Cited by 124 publications

(117 citation statements)

References 164 publications

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“…In AD, one of the most common neurodegenerative disorders, some alterations in the endo/lysosomal path ways have been described (reviewed elsewhere 157,158 ). The amyloid precursor protein (APP) is cleaved by β and γ secretases into amyloid β peptide (Aβ) fragments, particularly Aβ40 and Aβ42 (ReF.…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

500

374

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| Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases -including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease -this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.

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Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

500

374

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“…Neuropathologically, AD is characterized by synaptic loss, the deposition of extracellular amyloid-β (Aβ) plaques, and the presence of intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decades, extensive research has focused on AD, and a plethora of mechanisms including neuroinflammation [48], defects in mitochondrial dynamics and function [49], and autophagy failure [50] have been proposed to contribute to AD neurodegeneration. A pathological accumulation of autophagosomes has been observed in neocortical biopsies of AD patients [51], which has been attributed to the aberrant transport and/or acidification of autophagic vacuoles, in turn preventing their efficient clearance of lysosomes [51,52].…”

Section: Autophagy In the Central Nervous System (Cns)mentioning

confidence: 99%

Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

Plaza-Zabala

Sierra-Torre

Sierra

2017

IJMS

265

216

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Abstract:Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health and survival. However, we propose that the (dys)regulation of autophagy in microglia also affects innate immune functions such as phagocytosis and inflammation, which in turn contribute to the pathophysiology of aging and neurodegenerative diseases. Herein, we first describe the basic concepts of autophagy and its regulation, discuss key aspects for its accurate monitoring at the experimental level, and summarize the evidence linking autophagy impairment to CNS senescence and disease. We focus on acute, chronic, and autoimmunity-mediated neurodegeneration, including ischemia/stroke, Alzheimer's, Parkinson's, and Huntington's diseases, and multiple sclerosis. Next, we describe the actual and potential impact of autophagy on microglial phagocytic and inflammatory function. Thus, we provide evidence of how autophagy may affect microglial phagocytosis of apoptotic cells, amyloid-β, synaptic material, and myelin debris, and regulate the progression of age-associated neurodegenerative diseases. We also discuss data linking autophagy to the regulation of the microglial inflammatory phenotype, which is known to contribute to age-related brain dysfunction. Overall, we update the current knowledge of autophagy and microglia, and highlight as yet unexplored mechanisms whereby autophagy in microglia may contribute to CNS disease and senescence.

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“…Interestingly, other neurodegenerative diseases have been linked to autophagy-lysosome dysfunction mediating accumulation of toxic protein aggregates 47–49 . Specifically, mutant Huntingtin has been reported to also inhibit autophagosome-lysosome fusion in Huntington’s disease 50 , opening fascinating new scenarios of common pathogenic mechanisms across different diseases.…”

Section: Discussionmentioning

confidence: 99%

Kinase inhibition of G2019S-LRRK2 restores autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions

Obergasteiger

Frapporti

Lamonaca

et al. 2019

Preprint

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words)The Parkinson´s disease (PD)-associated kinase Leucine-Rich Repeat Kinase 2 (LRRK2) is a potent modulator of autophagy and impacts on lysosome biology and function, but unclarity exists on the precise mechanics of its role and the direction of this modulation. LRRK2 is also involved in the degradation of pathological alpha-synuclein, with pathogenic mutations precipitating neuropathology in cellular and animal models of PD, and most LRRK2 familial cases manifesting with Lewy neuropathology. Defects in autophagic processing and lysosomal degradation of alpha-synuclein have been postulated to underlie its accumulation and onset of neuropathology. Thus, it is critical to reconcile these independent pieces of information to obtain a comprehensive knowledge on LRRK2-associated pathology that could also be generalized to the idiopathic disease. Here, we report a focused investigation on the role of PD-causing G2019S-LRRK2 in the autophagy-lysosome pathway in a recombinant cell line model. Initially, we evaluated the effect of LRRK2 expression on autophagy-related transcriptome. Then, we found that G2019S-LRRK2 leads to accumulation of autophagosomes with no net effect on autophagy induction. This is linked to abnormalities in lysosome morphology and proteolytic activity that are associated with a decrease in the successful formation of autolysosomes. Despite some of these features being shared by WT-LRRK2, alpha-synuclein intracellular inclusions are specifically found in G2019S-LRRK2 cells. Pharmacological kinase inhibition is capable of rescuing defects in the autophagy-lysosome pathway and reducing the number of inclusions. Notably, this effect is prevented by upstream blockade of autophagosome-lysosome fusion events, highlighting this step of the process as critical for alpha-synuclein clearance. Mutations in the Lrrk2 gene cause late-onset, familial Parkinson´s disease (PD) with variable penetrance that is clinically indistinguishable from idiopathic PD (iPD) but with pleomorphic pathology 1 . However, the G2019S mutation is singularly the most common genetic cause of PD worldwide, with an incidence up to 40% in specific populations 2,3 , and mostly presents with alpha-synuclein (aSyn) Lewy neuropathology at autopsy 4 . The gene codes for Leucine-Rich Repeat Kinase 2 (LRRK2), a large multidomain protein with two distinct enzymatic domains (GTPase and kinase) in close vicinity to each other 5 . The PDlinked mutations reside in this enzymatic core with G2019S located in the kinase domain and reported to increase kinase activity 6 . The cellular roles impacted by LRRK2 are varied, with stronger consensus on synaptic transmission 7 , vesicle trafficking 8 and autophagy 9 . Interestingly, these pathways might converge in neuronal biology and function 10 . Several independent investigations demonstrated that LRRK2 acts at different stages of the autophagy-lysosome pathway, with some conflicting results on the direction of this modulation 9 . Indications include a kinase-dependent role of LRRK2 in the modulation of...

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Endo‐lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?

Cited by 124 publications

References 164 publications

Lysosomes as a therapeutic target

Lysosomes as a therapeutic target

Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

Kinase inhibition of G2019S-LRRK2 restores autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions

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