An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a Retromer Trafficking Defect

Qureshi, Yasir H.; Patel, Vivek M.; Berman, Diego E.; Kothiya, Milankumar; Neufeld, Jessica L.; Vardarajan, Badri N.; Tang, Min; Reyes‐Dumeyer, Dolly; Lantigua, Rafael; Medrano, Martin; Jiménez-Velázquez, Ivonne J.; Small, Scott A.; Reitz, Christiane

doi:10.1128/mcb.00011-18

Cited by 37 publications

(37 citation statements)

References 32 publications

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“…These findings support the hypothesis that the TPT-dependent changes in tau phosphorylation were secondary to a better turn-over and degradation of this protein resulting from the restoration of the retromer complex trafficking and sorting functions. Thus, having observed a significant increase in the CTSD and its receptor CI-MPR we speculate that the higher availability of this protease, previously involved in tau degradation [29], could be responsible for the lower levels of pathological tau in the treated mice [30].…”

Section: Discussionmentioning

confidence: 84%

A pharmacological chaperone improves memory by reducing Aβ and tau neuropathology in a mouse model with plaques and tangles

Chiu

Ramanjulu

et al. 2020

Mol Neurodegeneration

100

108

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Background: The vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex system, an ubiquitous multiprotein assembly responsible for sorting and trafficking protein cargos out of the endosomes. VPS35 can regulate APP metabolism and Aβ formation, and its levels are reduced in Alzheimer's disease (AD) brains. We and others demonstrated that VPS35 genetic manipulation modulates the phenotype of mouse models of AD. However, the translational value of this observation remains to be investigated. Methods: Triple transgenic mice were randomized to receive a pharmacological chaperone, which stabilizes the retromer complex, and the effect on their AD-like phenotype assessed. Results: Compared with controls, treated mice had a significant improvement in learning and memory, an elevation of VPS35 levels, and improved synaptic integrity. Additionally, the same animals had a significant decrease in Aβ levels and deposition, reduced tau phosphorylation and less astrocytes activation. Conclusions: Our study demonstrates that the enhancement of retromer function by pharmacological chaperones is a potentially novel and viable therapy against AD.

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Section: Discussionmentioning

confidence: 84%

A pharmacological chaperone improves memory by reducing Aβ and tau neuropathology in a mouse model with plaques and tangles

Chiu

Ramanjulu

et al. 2020

Mol Neurodegeneration

100

108

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“…Standard staining and microscopy techniques were used, as described previously 34,43–45 with some modifications. All washes were done with PBS (1X-PBS containing 0.01% Sodium Azide).…”

Section: Methodsmentioning

confidence: 99%

Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus

Qureshi

Berman

Klein

et al. 2019

Preprint

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Retromer has emerged as a master conductor of endosomal trafficking, and VPS35 and other retromer-related proteins are found to be deficient in late-onset Alzheimer's disease (AD). Depleting VPS35 in neurons impairs retromer function, affecting for example the trafficking of the amyloid-precursor protein (APP) and the glutamate receptor GluA1. Whether VPS35 repletion, after chronic in vivo depletion, can rescue these impairments remains unknown. Here we set out to address this question by using a viral vector approach for VPS35 repletion. First, we completed a series of studies using neuronal cultures in order to optimize AAV9-VPS35 delivery, and to understand how exogenous VPS35 expression affects its endogenous levels as well as its binding to other retromer proteins. Next, we completed a series of studies in wildtype mice to determine the optimum protocol for in vivo delivery of AAV9-VPS35 to the hippocampus. We relied on this information to deliver AAV9-VPS35 to the hippocampus of mice genetically engineered to have chronic, neuronal-selective, VPS35 depletion.VPS35 repletion in the hippocampus was found to normalize APP cleavage and to restore glutamate receptor levels. Unexpectedly, chronic VPS35 depletion in neurons caused glial activation, similar to the pattern observed in AD, which was also partially normalized by VPS35 repletion. Taken together, these studies strengthen the mechanistic link between retromer and AD, and have therapeutic implications.

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“…Finally, another CaMBP, CaM-dependent protein kinase type 1D, was present in decreased amounts in brain samples from CLN4 disease patients [ 10 ]. Interestingly, CaMKII and other CaMBPs play a central role in the progression of Alzheimer’s disease and recent work has linked Alzheimer’s to mutations in CLN5 [ 34 , 35 ]. However, how these CaMBPs affect NCL related pathways has yet to be studied.…”

Section: Ncl Proteins Influence Cellular Pathways That Are Regulatmentioning

confidence: 99%

Neuronal Ceroid Lipofuscinoses: Connecting Calcium Signalling through Calmodulin

Mathavarajah

O’Day

Huber

2018

Cells

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Despite the increased focus on the role of calcium in the neuronal ceroid lipofuscinoses (NCLs, also known as Batten disease), links between calcium signalling and the proteins associated with the disease remain to be identified. A central protein in calcium signalling is calmodulin (CaM), which regulates many of the same cellular processes affected in the NCLs. In this study, we show that 11 of the 13 NCL proteins contain putative CaM-binding domains (CaMBDs). Many of the missense mutations documented from NCL patients overlap with the predicted CaMBDs and are often key residues of those domains. The two NCL proteins lacking such domains, CLN7 and CLN11, share a commonality in undergoing proteolytic processing by cathepsin L, which contains a putative CaMBD. Since CaM appears to have both direct and indirect roles in the NCLs, targeting it may be a valid therapeutic approach for treating the disease.

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An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a Retromer Trafficking Defect

Cited by 37 publications

References 32 publications

A pharmacological chaperone improves memory by reducing Aβ and tau neuropathology in a mouse model with plaques and tangles

A pharmacological chaperone improves memory by reducing Aβ and tau neuropathology in a mouse model with plaques and tangles

Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus

Neuronal Ceroid Lipofuscinoses: Connecting Calcium Signalling through Calmodulin

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