Model‐guided microarray implicates the retromer complex in Alzheimer's disease

Small, Scott A.; Kent, Kelly; Pierce, Aimee; Leung, Conrad L.; Kang, Min Suk; Okada, Hirokazu; Honig, Lawrence S.; Vonsattel, Jean Paul; Kim, Tae Wan

doi:10.1002/ana.20667

Cited by 390 publications

(456 citation statements)

References 66 publications

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“…The finding that loss of PI(3,5)P 2 leads to neurodegeneration may be directly linked to recent discoveries that some forms of Alzheimer's disease correlate with defects in SORL1 (42) and Vps35 (43), which function in the same pathway. Vps35 is part of the retromer complex and in humans is required to form tubular carriers from the endosomes that travel by retrograde traffic to the trans-Golgi network (reviewed in ref.…”

Section: Discussionmentioning

confidence: 96%

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

Zhang¹,

Zolov²,

Chow³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

196

256

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The signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), likely functions in multiple signaling pathways. Here, we report the characterization of a mouse mutant lacking Vac14, a regulator of PI(3,5)P 2 synthesis. The mutant mice exhibit massive neurodegeneration, particularly in the midbrain and in peripheral sensory neurons. Cell bodies of affected neurons are vacuolated, and apparently empty spaces are present in areas where neurons should be present. Similar vacuoles are found in cultured neurons and fibroblasts. Selective membrane trafficking pathways, especially endosome-to-TGN retrograde trafficking, are defective. This report, along with a recent report on a mouse with a null mutation in Fig4, presents the unexpected finding that the housekeeping lipid, PI(3,5)P 2, is critical for the survival of neural cells.T he low-abundance signaling lipids, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P 2 ) and phosphatidylinositol 5-phosphate (PI(5)P), were discovered relatively recently (1-3). Because of their low abundance and the limited number of tools available for their study, relatively little is known about these lipids.An interesting property of PI(3,5)P 2 occurs in yeast, where a stimulus of hyperosmotic shock induces dramatic and transient changes in the levels of PI(3,5)P 2 . The levels of PI(3,5)P 2 transiently rise Ͼ20-fold (4). Within 1 minute, the levels rise 5-fold; by 5 minutes, they increase Ͼ20-fold; there is a short plateau of 10 min, and then PI(3,5)P 2 levels decrease at a rate similar to their increase. The rapid decrease in PI(3,5)P 2 levels occurs even though the cells remain in hyperosmotic media. Vacuole volume undergoes transient changes that parallel PI(3,5)P 2 levels. That these rapid and transient changes occur even in the presence of a sustained stimulus strongly suggests that PI(3,5)P 2 plays a major role in signaling pathways related to adaptation.Several proteins are required for the synthesis and turnover of PI(3,5)P 2 . PI(3,5)P 2 is synthesized from PI(3)P by the PI(3)P 5-kinase Fab1/PIKfyve/PIP5K3 (5, 6). Fab1 is stimulated by a regulatory complex that contains Vac14 (7, 8) and Fig4 (4, 9). Surprisingly, the Vac14/Fig4 complex plays two opposing roles in the regulation of steady-state levels of PI(3,5)P 2 . Vac14/Fig4 both activate Fab1 and also function in the breakdown of PI(3,5)P 2 through the lipid phosphatase activity of Fig4 (4, 9-11).In mammals, generation of PI(3,5)P 2 is predicted to impact PI(5)P production. In vitro studies have shown that PI(5)P can be generated from PI(3,5)P 2 through the PI(3,5)P 2 3-phosphatase activity of members of the myotubularin family and related proteins including MTM1, MTMR1, MTMR2, MTMR3, MTMR6, and hJUMPY/MTMR14 (12-15). In addition, PIKfyve/Fab1 can generate both PI(3,5)P 2 and PI(5)P in vitro (16). The source of PI(5)P in vivo has not been established. However, the generation of PI(5)P from either pathway requires PIKfyve/ Fab1 activity, either to produce the substrate for myotubularin [PI(3,5)P 2 ] or to produce PI(5...

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Section: Discussionmentioning

confidence: 96%

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

Zhang¹,

Zolov²,

Chow³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

196

256

View full text Add to dashboard Cite

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“…In attempting to address the analytic challenges of microarray, we were guided by our previous studies that used microarray to identify retromer trafficking defects as pathogenic in late-onset Alzheimer's disease (AD) (26,27). First, we needed to identify neighboring regions within the same brain structure, differentially affected and resistant to PD.…”

Section: Discussionmentioning

confidence: 99%

“…For example, in our previous studies, imaging-guided microarray applied to AD identified deficiencies in the retromer trafficking pathway (27). However, only by systematically manipulating retromer-related molecules-in cell culture (27), animal models (26)-and by linking genetic variance to the disease in human patients (30), was this trafficking pathway pathogenically linked to AD (31).…”

Section: Discussionmentioning

confidence: 99%

Polyamine pathway contributes to the pathogenesis of Parkinson disease

Lewandowski¹,

Verbitsky

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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129

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The full complement of molecular pathways contributing to the pathogenesis of Parkinson disease (PD) remains unknown. Here we address this issue by taking a broad approach, beginning by using functional MRI to identify brainstem regions differentially affected and resistant to the disease. Relying on these imaging findings, we then profiled gene expression levels from postmortem brainstem regions, identifying a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a range of studies were completed to support the pathogenicity of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology, we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, whereas Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, to test for a genetic link, we sequenced the SAT1 gene and a rare but unique disease-associated variant was identified. Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis.functional MRI | SAT1 | brainstem

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“…To date, the most disease-relevant among these trafficked proteins is APP. A few years ago, by using model-guided microarray techniques, our laboratory first identified deficiencies in the levels of the core retromer component Vps35 in the hippocampus of AD brains, suggesting a possible involvement of retromer function and trafficking in the pathogenic processing of APP [15]. In addition, protein levels of Vps26 were also reduced in the entorhinal cortex of patients with AD.…”

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confidence: 99%

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

et al. 2015

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The retromer is an evolutionary conserved multiprotein complex involved in the sorting and retrograde trafficking of cargo from endosomal compartments to the Golgi network and to the cell surface. The neuronal retromer traffics the amyloid precursor protein away from the endosomes, a site where amyloid precursor protein is enzymatically cleaved into pathogenic fragments in Alzheimer's disease. In recent years, deficiencies in retromer-mediated transport have been implicated in several neurological and non-neurological diseases, including Parkinson's disease, suggesting that improving the efficacy of the retromer trafficking pathway would result in decreased pathology. We recently identified a new family of small molecules that appear to stabilize the interaction between members of the retromer complex and enhance its function in neurons: the retromer pharmacological chaperones. Here we discuss the role of these molecules in the improvement of retromer trafficking and endosomal dysfunction, as well as their potential as therapeutics for neurological and non-neurological disorders.

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Model‐guided microarray implicates the retromer complex in Alzheimer's disease

Cited by 390 publications

References 66 publications

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

Polyamine pathway contributes to the pathogenesis of Parkinson disease

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

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