Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing

Boland, Barry; Yu, Wen H.; Corti, Olga; Mollereau, Bertrand; Henriques, Alexandre Cruz; Bézard, Erwan; Pastores, GM; Rubinsztein, David C.; Nixon, Ralph A.; Duchen, Michael R.; Mallucci, Giovanna R.; Kroemer, Guido; Levine, Beth; Eskelinen, Eeva‐Liisa; Mochel, Fanny; Spedding, Michael; Louis, Caroline; Martin, Olivier R.; Millan, Mark J.

doi:10.1038/nrd.2018.109

Cited by 415 publications

(358 citation statements)

References 351 publications

(807 reference statements)

Supporting

Mentioning

324

Contrasting

Unclassified

Order By: Relevance

“…Insufficient clearance of neurotoxic proteins by the autophagy-lysosomal network has been implicated in numerous neurodegenerative disorders 152 . In disorders such as AD, Huntington disease (HD) and PD, modi fied or misfolded proteins abnormally accumulate in specific regions of the brain.…”

Section: Neurodegenerative Disordersmentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

500

374

View full text Add to dashboard Cite

| 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.

show abstract

Section: Neurodegenerative Disordersmentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

500

374

View full text Add to dashboard Cite

show abstract

“…It has also been reported that there is diurnal variation of iron content in the ventral midbrain (Unger, Earley, & Beard, 2009), supporting the existence of mechanisms for iron export from the brain to the systemic compartment. It has been suggested that the glymphatic system in the brain (Iliff et al, 2012;Papadopoulos & Verkman, 2013;Louveau et al, 2015;Trevaskis, Kaminskas, & Porter, 2015;Boland et al, 2018) may be one of the routes by which transition metals including iron are transported and cleared from the brain via convective bulk flow of interstitial fluid, possibly mediated by astrocytic end-feet-expressed aquaporin-4 (Aqp4) water channels (Ashraf et al, 2018). However, the available information about if and how this system facilitates iron transport remains limited at present and further studies are needed.…”

Section: Iron Transport Across the Blood-cerebrospinal Fluid Barmentioning

confidence: 99%

Brain iron transport

Qian

2019

Biological Reviews

View full text Add to dashboard Cite

Brain iron is a crucial participant and regulator of normal physiological activity. However, excess iron is involved in the formation of free radicals, and has been associated with oxidative damage to neuronal and other brain cells. Abnormally high brain iron levels have been observed in various neurodegenerative diseases, including neurodegeneration with brain iron accumulation, Alzheimer's disease, Parkinson's disease and Huntington's disease. However, the key question of why iron levels increase in the relevant regions of the brain remains to be answered. A full understanding of the homeostatic mechanisms involved in brain iron transport and metabolism is therefore critical not only for elucidating the pathophysiological mechanisms responsible for excess iron accumulation in the brain but also for developing pharmacological interventions to disrupt the chain of pathological events occurring in these neurodegenerative diseases. Numerous studies have been conducted, but to date no effort to synthesize these studies and ideas into a systematic and coherent summary has been made, especially concerning iron transport across the luminal (apical) membrane of the capillary endothelium and the membranes of different brain cell types. Herein, we review key findings on brain iron transport, highlighting the mechanisms involved in iron transport across the luminal (apical) as well as the abluminal (basal) membrane of the blood–brain barrier, the blood–cerebrospinal fluid barrier, and iron uptake and release in neurons, oligodendrocytes, astrocytes and microglia within the brain. We offer suggestions for addressing the many important gaps in our understanding of this important topic, and provide new insights into the potential causes of abnormally increased iron levels in regions of the brain in neurodegenerative disorders.

show abstract

“…Neuronal proteostasis is continuously maintained by endoplasmic reticulum (ER)-mediated mechanisms including the unfolded protein response (UPR). Protein aggregates which are formed in spite of this are removed from neurons by autophagy [19,20]. In AD, ER function and autophagy are compromised due to both NFT buildup and A␤ accumulation [21].…”

Section: Introductionmentioning

confidence: 99%

Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer’s Disease Brain

Yamoah

Tripathi

Sechi

et al. 2020

JAD

View full text Add to dashboard Cite

Granulovacuolar degeneration (GVD) occurs in Alzheimer's disease (AD) brain due to compromised autophagy. Endoplasmic reticulum (ER) function and RNA binding protein (RBP) homeostasis regulate autophagy. We observed that the ER chaperones Glucose -regulated protein, 78 KDa (GRP78/BiP), Sigma receptor 1 (SigR1), and Vesicle-associated membrane protein associated protein B (VAPB) were elevated in many AD patients' subicular neurons. However, those neurons which were affected by GVD showed lower chaperone levels, and there was only minor co-localization of chaperones with GVD bodies (GVBs), suggesting that neurons lacking sufficient chaperone-mediated proteostasis enter the GVD pathway. Consistent with this notion, granular, incipient pTau aggregates in human AD and pR5 tau transgenic mouse neurons were regularly co-localized with increased chaperone immunoreactivity, whereas neurons with mature neurofibrillary tangles lacked both the chaperone buildup and significant GVD. On the other hand, APP/PS1 (APPswe/PSEN1dE9) transgenic mouse hippocampal neurons that are devoid of pTau accumulation displayed only few GVBs-like vesicles, which were still accompanied by prominent chaperone buildup. Identifying a potential trigger for GVD, we found cytoplasmic accumulations of RBPs including Matrin 3 and FUS as well as stress granules in GVBs of AD patient and pR5 mouse neurons. Interestingly, we observed that GVBs containing aggregated pTau and pTDP-43 were consistently co-localized with the exosomal marker Flotillin 1 in both AD and pR5 mice. In contrast, intraneuronal 82E1-immunoreactive amyloid-␤ in human AD and APP/PS1 mice only rarely co-localized with Flotillin 1-positive exosomal vesicles. We conclude that altered chaperone-mediated ER protein homeostasis and impaired autophagy manifesting in GVD are linked to both pTau and RBP accumulation and that some GVBs might be targeted to exocytosis.

show abstract

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing

Cited by 415 publications

References 351 publications

Lysosomes as a therapeutic target

Lysosomes as a therapeutic target

Brain iron transport

Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer’s Disease Brain

Contact Info

Product

Resources

About