Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Lotfi, Parisa; Tse, Dennis Y.; Ronza, Alberto di; Seymour, Michelle L.; Martano, Giuseppe; Cooper, Jonathan D.; Pereira, Fred A.; Passafaro, Maria; Wu, Samuel M.; Sardiello, Marco

doi:10.1080/15548627.2018.1474313

Cited by 89 publications

(73 citation statements)

References 74 publications

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“…Recent studies focused on activation of TFEB, a master regulator of lysosomal biogenesis and function (48,49), indicate that lysosomal enhancement may counteract disease progression in animal models of lysosomal storage disorders, including a model of Batten disease (50,51).…”

Section: Discussionmentioning

confidence: 99%

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Bajaj

Ronza

Zheng³

et al. 2019

Preprint

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Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and transferred to the Golgi complex by interaction with the Batten disease protein CLN8. Here we investigated the relationship of this pathway with CLN6, an ER-associated protein of unknown function that is defective in a different Batten disease subtype. Experiments focused on protein interaction and trafficking identified CLN6 as an obligate component of a CLN6-CLN8 complex (herein referred to as EGRESS: ER-to-Golgi relaying of enzymes of the lysosomal system) which recruits lysosomal enzymes at the ER to promote their Golgi transfer. Simultaneous deficiency of CLN6 and CLN8 did not aggravate mouse pathology compared to the single deficiencies, indicating that the EGRESS complex works as a functional unit. Mutagenesis experiments showed that the second luminal loop of CLN6 is required for the interaction of CLN6 with the enzymes but dispensable for interaction with CLN8, and in vitro and in vivo studies showed that CLN6 deficiency results in inefficient ER export of lysosomal enzymes and diminished levels of the enzymes at the lysosome. These results identify CLN6 and the EGRESS complex as key players in lysosome biogenesis and shed light on the molecular etiology of Batten disease caused by defects in CLN6.

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Section: Discussionmentioning

confidence: 99%

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Bajaj

Ronza

Zheng³

et al. 2019

Preprint

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“…The behavioral alterations reported in MPS III mice are variable. Three-week-old mixed-strain MPS IIIA mice [70], 3 to 10-month-old congenic MPS IIIA mice [64,78,85,86], 3 to 8-month-old MPS IIIB mice [76,[87][88][89]] and 6 to 8-month-old MPS IIIC mice [66] have shown hyperactivity in the Open Field (OF) test as compared to control counterparts. For some of these strains, reduced activity was recorded as the disease progressed.…”

Section: Animal Models Of Mps IIImentioning

confidence: 99%

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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The mucopolysaccharidoses (MPS) are a group of diseases caused by the lysosomal accumulation of glycosaminoglycans, due to genetic deficiencies of enzymes involved in their degradation. MPS III or Sanfilippo disease, in particular, is characterized by early-onset severe, progressive neurodegeneration but mild somatic involvement, with patients losing milestones and previously acquired skills as the disease progresses. Despite being the focus of extensive research over the past years, the links between accumulation of the primary molecule, the glycosaminoglycan heparan sulfate, and the neurodegeneration seen in patients have yet to be fully elucidated. This review summarizes the current knowledge on the molecular bases of neurological decline in Sanfilippo disease. It emerges that this deterioration results from the dysregulation of multiple cellular pathways, leading to neuroinflammation, oxidative stress, impaired autophagy and defects in cellular signaling. However, many important questions about the neuropathological mechanisms of the disease remain unanswered, highlighting the need for further research in this area.

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“…TFEB activation in MPS IIIB mice via oral administration of trehalose prevented retinal degeneration, attenuated vision loss, and reduced both neuroinflammation and the load of autophagic vacuoles in brain cells (Lotfi et al . ). Trehalose treatment also elongated the lifespan of MPS IIIB mice (Lotfi et al .…”

Section: Therapeutic Effects Of Tfeb‐mediated Enhancement Of the Automentioning

confidence: 97%

“…Trehalose treatment also elongated the lifespan of MPS IIIB mice (Lotfi et al . ). Since no other enzymes similar to α‐N‐acetylglucosaminidase are known that could compensate for its loss, it is likely that the clearance effect obtained upon TFEB activation was mainly mediated by lysosomal exocytosis, as seen for exogenous TFEB expression in other models of lysosomal enzyme deficiencies.…”

Section: Therapeutic Effects Of Tfeb‐mediated Enhancement Of the Automentioning

confidence: 97%

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Lysosome biogenesis in health and disease

Bajaj

Lotfi

Pal

et al. 2018

Journal of Neurochemistry

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107

116

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This review focuses on the pathways that regulate lysosome biogenesis and that are implicated in numerous degenerative storage diseases, including lysosomal storage disorders and late-onset neurodegenerative diseases. Lysosomal proteins are synthesized in the endoplasmic reticulum and trafficked to the endolysosomal system through the secretory route. Several receptors have been characterized that execute post-Golgi trafficking of lysosomal proteins. Some of them recognize their cargo proteins based on specific amino acid signatures, others based on a particular glycan modification that is exclusively found on lysosomal proteins. Nearly all receptors serving lysosome biogenesis are under the transcriptional control of transcription factor EB (TFEB), a master regulator of the lysosomal system. TFEB coordinates the expression of lysosomal hydrolases, lysosomal membrane proteins, and autophagy proteins in response to pathways sensing lysosomal stress and the nutritional conditions of the cell among other stimuli. TFEB is primed for activation in lysosomal storage disorders but surprisingly its function is impaired in some late-onset neurodegenerative storage diseases like Alzheimer's and Parkinson's, because of specific detrimental interactions that limit TFEB expression or activation. Thus, disrupted TFEB function presumably plays a role in the pathogenesis of these diseases. Multiple studies in animal models of degenerative storage diseases have shown that exogenous expression of TFEB and pharmacological activation of endogenous TFEB attenuate disease phenotypes. These results highlight TFEB-mediated enhancement of lysosomal biogenesis and function as a candidate strategy to counteract the progression of these diseases. This article is part of the Special Issue "Lysosomal Storage Disorders".

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Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Cited by 89 publications

References 74 publications

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Lysosome biogenesis in health and disease

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